Journal articles on the topic 'TGFβ1 treatment'
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Budhu, Sadna, Aditi Gupta, Kelly Fitzgerald, Rachel Giese, Adam Michel, Aliya Holland, Luis Felipe Campesato, et al. "567 Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of stroma poor cancers." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A596. http://dx.doi.org/10.1136/jitc-2021-sitc2021.567.
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BackgroundTGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. There are three isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3), which are secreted by immune and non-immune cells as an inactive latent complex. Depending on the local context and players, TGFβ can adopt opposing roles in carcinogenesis and in modulating the immune system. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-rich tumors.MethodsWe examined expression of TGFβ1 and TGFβ3 isoforms on immune cells in two stroma-poor mouse tumor models (B16 melanoma and CT26 colon carcinoma) and investigated the anti-tumor efficacy of antibodies that block TGFβ1 and TGFβ3 in these two models.ResultsDepending on local expression of TGFβ isoforms, specific inhibition of either TGFβ1 or TGFβ3 may be effective. The ”TGFβ signature” of CT26 colon carcinoma is defined by TGFβ1 expression on immune cells and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both TGFβ1 or TGFβ3 isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. We show that the mechanism of tumor growth delay is enhanced CD8+ T cell activation and effector function. In addition, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control and survival.ConclusionsOur findings suggests that expression of TGFβ isoforms in the TME is variable in different tumor types and their expression may be used to predict anti-tumor responses to TGFβ inhibition. Isoform specific TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor regression alone or in combination with immune checkpoint blockade.
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Budhu, Sadna, Aditi Gupta, Rachel Giese, Jacques van Snick, Catherine Uyttenhove, Gerd Ritter, Jedd D. Wolchok, and Taha Merghoub. "Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 136.23. http://dx.doi.org/10.4049/jimmunol.202.supp.136.23.
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Abstract TGFβ is a pleotropic cytokine, which has emerged as a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. There are three isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3), which are secreted by immune and nonimmune cells as an inactive latent complex. Depending on the local context and players, TGFβ can adopt opposing roles in carcinogensis and in modulating the immune system. However, the expression of TGFβ isoforms within the tumor microenvironment and isoform specific inhibition remains to be investigated. The main source of TGFβ isoforms in the tumor microenvironment of B16 melanoma are infiltrating immune cells, with TGFβ1 and TGFβ3 being highly expressed on myeloid and dendritic cells. The CD45− population from B16 tumors demonstrated a lower expression of both TGFβ isoforms. Compared to untreated control animals, anti-TGFβ3 therapy resulted in the greatest delay in B16 tumor growth, followed by anti-TGFβ1 therapy and pan-TGFβ blockade. However, none of the therapies resulted in improved overall survival. Similar results were achieved in a 4T1 breast model. T cell functional assays demonstrated that anti-TGFβ3 resulted in CD8+ T cells with greater cytolytic ability as they showed higher granzyme B expression and killing against B16 cells when plated ex-vivo. Anti-TGFβ1 treatment resulted in greater interferon-γ production by CD8+ T cells, suggesting an increase in antigen-specificity. Isoform specific TGFβ inhibition in combination with immune checkpoint blockade demonstrated improved tumor control and survival. This provides rationale for the use of anti-TGFβ therapy in stroma poor tumors, such as melanoma, and for its potential to enhance the effectiveness of existing therapies.
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Shynlova, Oksana, Prudence Tsui, Anna Dorogin, B. Lowell Langille, and Stephen J. Lye. "The expression of transforming growth factor β in pregnant rat myometrium is hormone and stretch dependent." Reproduction 134, no. 3 (September 2007): 503–11. http://dx.doi.org/10.1530/rep-07-0004.
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From a quiescent state in early pregnancy to a highly contractile state in labor, the myometrium displays tremendous growth and remodeling. We hypothesize that the transforming growth factor β (TGFβ) system is involved in the differentiation of pregnant myometrium throughout gestation and labor. Furthermore, we propose that during pregnancy the mechanical and hormonal stimuli play a role in regulating myometrial TGFβs. The expression of TGFβ1-3 mRNAs and proteins was examined by real-time PCR, Western immunoblot, and localized with immunohistochemistry in the rat uterus throughout pregnancy and labor. Tgfβ1-3 genes were expressed differentially in pregnant myometrium. Tgfβ2 gene was not affected by pregnancy, whereas the Tgfβ1 gene showed a threefold increase during the second half of gestation. In contrast, we observed a dramatic bimodal change in Tgfβ3 gene expression throughout pregnancy. Tgfβ3 mRNA levels first transiently increased at mid-gestation (11-fold on day 14) and later at term (45-fold at labor, day 23). Protein expression levels paralleled the changes in mRNA. Treatment of pregnant rats with the progesterone (P4) receptor antagonist RU486 induced premature labor on day 19 and increased Tgfβ3 mRNA, whereas artificial maintenance of elevated P4 levels at late gestation (days 20–23) caused a significant decrease in the expression of Tgfβ3 gene. In addition, Tgfβ3 was up-regulated specifically in the gravid horn of unilaterally pregnant rats subjected to a passive biological stretch imposed by the growing fetuses, but not in the empty horn. Collectively, these data indicate that the TGFβ family contributes in the regulation of myometrial activation at term integrating mechanical and endocrine signals for successful labor contraction.
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Quintela, M., R. M. SeñarÍs, and C. Diéguez. "Transforming Growth Factor-βs Inhibit Somatostatin Messenger Ribonucleic Acid Levels and Somatostatin Secretion in Hypothalamic Cells in Culture*." Endocrinology 138, no. 10 (October 1, 1997): 4401–9. http://dx.doi.org/10.1210/endo.138.10.5467.
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Abstract Treatment of hypothalamic cells in monolayer culture with transforming growth factor-β1 (TGFβ1) significantly reduced both basal and cAMP-induced somatostatin messenger RNA (mRNA) levels and somatostatin secretion. This inhibitory effect was dose- and time-dependent and not mediated by glial cells, as it was also observed in glial-free hypothalamic cell cultures treated with cytosine arabinonucleoside. TGFβ2 and -β3 mimicked the actions of TGFβ1, which indicated that the three isoforms of the TGFβ family expressed in the central nervous system displayed similar effects on the somatostatinergic neurons. The blockade of synthesis of proteins with either cycloheximide or puromycin for 24 h prevented the inhibitory effect of TGFβ1 on somatostatin mRNA. This implied that the reduction of this mRNA by TGFβ1 required de novo protein synthesis. We next studied whether TGFβ1 acted at the transcriptional or posttranscriptional level by altering the stability of somatostatin mRNA. Examination of the rate of disappearance of somatostatin mRNA by Northern blot, after inhibition of mRNA transcription with either actinomycin D (AcD) or 5,6-dichloro-1β-ribofuranosyl benzimidazole revealed that TGFβ1 did reduce the stability of somatostatin mRNA. This effect was observed when we pretreated the cultures with TGFβ1 4 h before the addition of AcD, but not when we administered TGFβ1 simultaneously with AcD or 5,6-dichloro-1β-ribofuranosyl benzimidazole. Altogether these results demonstrated that the treatment of hypothalamic cells in culture with TGFβ1, TGFβ2, or TGFβ3 resulted in a decrease in somatostatin mRNA levels and somatostatin secretion. TGFβ1 reduced the steady state levels of somatostatin mRNA by inducing the synthesis of a protein (s), that appears to accelerate the degradation of the mRNA of somatostatin. Whether TGFβ1 has additional effects on the transcription of the somatostatin gene will require further study.
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Varricchio, Lilian, John Mascarenhas, Anna Rita Migliaccio, Maureen O'Connor-McCourt, Gilles Tremblay, Jean-François Denis, Camelia Iancu-Rubin, and Ronald Hoffman. "AVID200, a Potent Trap for TGF-β Ligands Inhibits TGF-β1 Signaling in Human Myelofibrosis." Blood 132, Supplement 1 (November 29, 2018): 1791. http://dx.doi.org/10.1182/blood-2018-99-116474.
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Abstract Myelofibrosis (MF) is caused by driver mutations which upregulate JAK/STAT signaling. The only curative treatment for MF is hematopoietic stem cell transplant. Ruxolitinib alleviates many of the symptoms in MF but does not significantly alter survival. There is, therefore, an urgent need for additional rational therapies for MF. Bone marrow fibrosis and collagen deposition are hallmarks of MF which have been attributed to megakaryocyte (MK) derived TGFβ, which also plays a role in myelo-proliferation. There are three isoforms of TGFβ (TGFβ1, β2, and β3). AVID200, which was constructed by fusing TGFβR ectodomains to IgG Fc regions, is a potent TGFβ trap with pM potency against two of the three TGFβ ligands, TGFβ1 and β3 (IC50 values of ~ 3 pM ). AVID200's IC50 for TGFβ2 is ~4,000-fold higher indicating that it has minimal activity against TGFβ2, which is desirable since TGFβ2 is a positive regulator of hematopoiesis. We explored the therapeutic potential of AVID200 by culturing MF or normal donor (ND) mononuclear cells (MNCs) first in the presence of stem cell factor and thrombopoietin (TPO) and then TPO alone in order to generate MK-enriched populations. Although the percentage of mature MKs from ND and MF MNCs was similar, the absolute number of CD41+/CD42+ MKs generated from MF MNCs was two-fold greater than ND MNCs. To determine the levels of TGFβ secreted by the MKs we screened MF and ND MNC conditioned media (CM). We observed significantly higher levels of TGFβ1 but not TGFβ2 and TGFβ3 in MF MK CM. The effects of AVID200 on MKs were then evaluated by measuring the levels of phosphorylated SMAD2. Treatment with 0.001 - 0.1 nM AVID200 decreased phosphorylation of SMAD2, suggesting that AVID200 blocks autocrine MK TGFβ signaling. The increased levels of TGFβ in MF patients promote the proliferation and deposition of collagen by mesenchymal stem cells (MSCs). Cellular proliferation of MSCs was evaluated following treatment with either recombinant TGFβ1 or ND/MF CM in the presence or absence of AVID200. In the absence of AVID200, both recombinant TGFβ1 and MK-derived CM increased the proliferation of MSCs by 1.4- and 1.6-fold respectively, which returned to basal levels with the addition of increasing concentrations of AVID200. These data indicate that AVID200 directly blocks the effect of TGFβ1 on MSCs. MF stroma is characterized by an increase in Type I collagen. We therefore examined if treatment with AVID200 interferes with the ability of TGFβ1 to induce collagen expression by MSCs. MSCs were cultured in presence of recombinant TGFβ1 alone or in combination with varying concentrations of AVID200 for 72 hours. Recombinant TGFβ1 alone induced an increase in COL1A1 mRNA expression as compared to untreated controls (p<0.01). Addition of AVID200 eliminated the TGFβ-mediated increase in COL1A1 expression in a dose dependent manner. ND and MF MK-derived CM also increased COL1A1 expression by MSCs as compared to un-treated controls (p<0.01) and that effect was eliminated by AVID200 treatment (p<0.01). We next demonstrated that TGFβ1 activated pSMAD2 in MSCs without affecting total SMAD2/3 expression and that SMAD2 phosphorylation was reduced by adding AVID200. Furthermore, AVID200 treatment decreased pSTAT3 which is associated with the ability of TGFβ to induce fibrosis. We next investigated the effect of AVID200 on MF hematopoiesis. Briefly, MNCs (which produce TGFβ) from two JAK2V617F+ MF patients were incubated with or without 50 nM of AVID200 and plated in semi-solid media. Treatment with AVID200 did not affect the overall number of colonies generated, but reduced the numbers of JAKV617F+ colonies while increasing the numbers of WT colonies: for PT1, there were 32% JAKV617F+ CFUs in untreated cultures (11 JAKV617F+/34 total colonies) versus 16% JAKV617F+ CFUs (7 JAKV617F+/42 total CFUs) in AVID200 treated cultures; for PT2 there were 100% JAKV617F+ CFUs in untreated cultures (37 JAKV617F+/37 total CFUs) versus 94% JAKV617F+ CFUs (49 JAK2V617F+/52 total CFUs) in AVID200 treated cultures. The in vivo effects of AVID200 on the development of MF in GATA1 low mice will be presented at the meeting. These data indicate that AVID200 selectively suppresses TGFβ1 signaling associated with the proliferation of MSCs and type I collagen synthesis, and depletes MF MNCs of JAK2V617F+progenitor cells. We conclude that AVID200 is a promising agent for treating MF patients which will be evaluated in a phase 1 clinical trial. Disclosures Mascarenhas: Novartis: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Iancu-Rubin:Incyte: Research Funding; Merck: Research Funding; Summer Road, LLC: Research Funding; Formation Biologics: Research Funding. Hoffman:Incyte: Research Funding; Summer Road: Research Funding; Merus: Research Funding; Janssen: Research Funding; Formation Biologics: Research Funding.
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Elsafadi, Mona, Muthurangan Manikandan, Sami Almalki, Mohammad Mobarak, Muhammad Atteya, Zafar Iqbal, Jamil Amjad Hashmi, et al. "TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton." Stem Cells International 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/6913594.
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TGFβ is a potent regulator of several biological functions in many cell types, but its role in the differentiation of human bone marrow-derived skeletal stem cells (hMSCs) is currently poorly understood. In the present study, we demonstrate that a single dose of TGFβ1 prior to induction of osteogenic or adipogenic differentiation results in increased mineralized matrix or increased numbers of lipid-filled mature adipocytes, respectively. To identify the mechanisms underlying this TGFβ-mediated enhancement of lineage commitment, we compared the gene expression profiles of TGFβ1-treated hMSC cultures using DNA microarrays. In total, 1932 genes were upregulated, and 1298 genes were downregulated. Bioinformatics analysis revealed that TGFβl treatment was associated with an enrichment of genes in the skeletal and extracellular matrix categories and the regulation of the actin cytoskeleton. To investigate further, we examined the actin cytoskeleton following treatment with TGFβ1 and/or cytochalasin D. Interestingly, cytochalasin D treatment of hMSCs enhanced adipogenic differentiation but inhibited osteogenic differentiation. Global gene expression profiling revealed a significant enrichment of pathways related to osteogenesis and adipogenesis and of genes regulated by both TGFβ1 and cytochalasin D. Our study demonstrates that TGFβ1 enhances hMSC commitment to either the osteogenic or adipogenic lineages by reorganizing the actin cytoskeleton.
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Feger, Martina, Ioana Alesutan, Tatsiana Castor, Sobuj Mia, Katharina Musculus, Jakob Voelkl, and Florian Lang. "Inhibitory Effect of NH4Cl Treatment on Renal Tgfß1 Signaling Following Unilateral Ureteral Obstruction." Cellular Physiology and Biochemistry 37, no. 3 (2015): 955–64. http://dx.doi.org/10.1159/000430222.
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Background/Aims: Consequences of obstructive nephropathy include tissue fibrosis, a major pathophysiological mechanism contributing to development of end-stage renal disease. Transforming growth factor β 1 (Tgfβ1) is involved in the progression of renal fibrosis. According to recent observations, ammonium chloride (NH4Cl) prevented phosphate-induced vascular remodeling, effects involving decrease of Tgfβ1 expression and inhibition of Tgfβ1-dependent signaling. The present study, thus, explored whether NH4Cl influences renal Tgfβ1-induced pro-fibrotic signaling in obstructive nephropathy induced by unilateral ureteral obstruction (UUO). Methods: UUO was induced for seven days in C57Bl6 mice with or without additional treatment with NH4Cl (0.28 M in drinking water). Transcript levels were determined by RT-PCR as well as protein abundance by Western blotting, blood pH was determined utilizing a blood gas and chemistry analyser. Results: UUO increased renal mRNA expression of Tgfb1, Tgfβ-activated kinase 1 (Tak1) protein abundance and Smad2 phosphorylation in the nuclear fraction of the obstructed kidney tissues, effects blunted in NH4Cl treated mice as compared to control treated mice. The mRNA levels of the transcription factors nuclear factor of activated T cells 5 (Nfat5) and SRY (sex determining region Y)-box 9 (Sox9) as well as of tumor necrosis factor α (Tnfα), interleukin 6 (Il6), plasminogen activator inhibitor 1 (Pai1) and Snai1 were up-regulated in the obstructed kidney tissues following UUO, effects again significantly ameliorated following NH4Cl treatment. Furthermore, the increased protein and mRNA expression of α-smooth muscle actin (α-Sma), fibronectin and collagen type I in the obstructed kidney tissues following UUO were significantly attenuated following NH4Cl treatment. Conclusion: NH4Cl treatment ameliorates Tgfβ1-dependent pro-fibrotic signaling and renal tissue fibrosis markers following obstructive nephropathy.
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Recouvreux, M. Victoria, M. Andrea Camilletti, Daniel B. Rifkin, and Graciela Díaz-Torga. "The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas." Journal of Endocrinology 228, no. 3 (December 23, 2015): R73—R83. http://dx.doi.org/10.1530/joe-15-0451.
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Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists (DAs). However, a subset of prolactinomas fails to respond to such therapies and is considered as DA-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. Transforming growth factor β1 (TGFβ1) is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFβ1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGFβ1 system including latent binding proteins, local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFβ receptors. Pituitary TGFβ1 activity and the expression of different components of the TGFβ1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFβ1 activity as well as reduced expression of several components of the TGFβ1 system. Therefore, restoration of TGFβ1 inhibitory activity represents a novel therapeutic approach to bypass dopamine action in DARPs. The aim of this review is to summarize the large literature supporting TGFβ1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGFβ1 activity as an effective treatment in experimental prolactinomas.
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Martin, Constance J., Abhishek Datta, Christopher Littlefield, Ashish Kalra, Christopher Chapron, Stefan Wawersik, Kevin B. Dagbay, et al. "Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape." Science Translational Medicine 12, no. 536 (March 25, 2020): eaay8456. http://dx.doi.org/10.1126/scitranslmed.aay8456.
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Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti–programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor–β (TGFβ) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFβ isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFβ isoform expressed in many types of human tumors, suggesting that TGFβ1 may be a key contributor to primary CBT resistance. To test whether selective TGFβ1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFβ1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti–PD-1 antibody in mice harboring syngeneic tumors refractory to anti–PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFβ1 was also effective in tumors expressing more than one TGFβ isoform. Combined SRK-181-mIgG1 and anti–PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFβ1 activation may avoid dose-limiting toxicities previously observed with pan-TGFβ inhibitors. These results establish a rationale for exploring selective TGFβ1 inhibition to overcome primary resistance to CBT.
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Peng, Fangfang, Baifang Zhang, Dongcheng Wu, Alistair J. Ingram, Bo Gao, and Joan C. Krepinsky. "TGFβ-induced RhoA activation and fibronectin production in mesangial cells require caveolae." American Journal of Physiology-Renal Physiology 295, no. 1 (July 2008): F153—F164. http://dx.doi.org/10.1152/ajprenal.00419.2007.
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Glomerular sclerosis of diverse etiologies is characterized by mesangial matrix accumulation, with transforming growth factor-β (TGFβ) an important pathogenic factor. The GTPase RhoA mediates TGFβ-induced matrix accumulation in some settings. Here we study the role of the membrane microdomain caveolae in TGFβ-induced RhoA activation and fibronectin upregulation in mesangial cells (MC). In primary rat MC, TGFβ1 time dependently increased RhoA and downstream Rho kinase activation. Rho pathway inhibition blocked TGFβ1-induced upregulation of fibronectin transcript and protein. TGFβ1-induced RhoA activation was prevented by disrupting caveolae with cholesterol depletion and rescued by cholesterol repletion. Compared with wild types, RhoA/Rho kinase activation was absent in MC lacking caveolae. Reexpression of caveolin-1 (and caveolae) restored these responses. Phosphorylation of caveolin-1 on Y14, effected by Src kinases, has been implicated in signaling responses. Overexpression of nonphosphorylatable caveolin-1 Y14A prevented TGFβ1-induced RhoA activation. TGFβ1 also activated Src, and its inhibition blocked RhoA activation. Furthermore, TGFβ1 led to association of RhoA and caveolin-1. This was prevented by Src or TGFβ receptor I inhibition, and by caveolin-1 Y14A overexpression. Last, fibronectin upregulation by TGFβ1 was blocked by Src inhibition, not seen in caveolin-1 knockout MC, and restored by caveolin-1 reexpression in the latter. TGFβ1-induced collagen I accumulation also required caveolae. TGFβ1-mediated Smad2/3 activation, however, did not require caveolae. We conclude that RhoA/Rho kinase mediates TGFβ-induced fibronectin upregulation. This requires caveolae and caveolin-1 interaction with RhoA. Interference with caveolin/caveolae or RhoA signaling thus represents a potential target for the treatment of fibrotic renal disease.
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Ueland, Thor, Tove Lekva, Kari Otterdal, Tuva B. Dahl, Nicoleta Cristina Olarescu, Anders P. Jørgensen, Kristian J. Fougner, Kim Brixen, Pål Aukrust, and J. Bollerslev. "Increased serum and bone matrix levels of transforming growth factor β1 in patients with GH deficiency in response to GH treatment." European Journal of Endocrinology 165, no. 3 (September 2011): 393–400. http://dx.doi.org/10.1530/eje-11-0442.
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ObjectivePatients with adult onset GH deficiency (aoGHD) have secondary osteoporosis, which is reversed by long-term GH substitution. Transforming growth factor β1 (TGFβ1 or TGFB1) is abundant in bone tissue and could mediate some effects of GH/IGFs on bone. We investigated its regulation by GH/IGF1in vivoandin vitro.Design and methodsThe effects of GH substitution (9–12 months, placebo controlled) on circulating and cortical bone matrix contents of TGFβ1 were investigated in patients with aoGHD. The effects of GH/IGF1 on TGFβ1 secretion in osteoblasts (hFOB), adipocytes, and THP-1 macrophages as well as the effects on release from platelets were investigatedin vitro.ResultsIn vivoGH substitution increased TGFβ1 protein levels in cortical bone and serum.In vitro, GH/IGF1 stimulation induced a significant increase in TGFβ1 secretion in hFOB. In contrast, no major effect of GH/IGF1 on TGFβ1 was found in adipocytes and THP-1 macrophages. Finally, a minor modifying effect on SFLLRN-stimulated platelet release of TGFβ1 was observed in the presence of IGF1.ConclusionGH substitution increases TGFβ1in vivoandin vitro, and this effect could contribute to improved bone metabolism during such therapy, potentially reflecting direct effect of GH/IGF1 on bone cells.
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Stasyk, Taras, Anna Dubrovska, Marta Lomnytska, Ihor Yakymovych, Christer Wernstedt, Carl-Henrik Heldin, Ulf Hellman, and Serhiy Souchelnytskyi. "Phosphoproteome Profiling of Transforming Growth Factor (TGF)-β Signaling: Abrogation of TGFβ1-dependent Phosphorylation of Transcription Factor-II-I (TFII-I) Enhances Cooperation of TFII-I and Smad3 in Transcription." Molecular Biology of the Cell 16, no. 10 (October 2005): 4765–80. http://dx.doi.org/10.1091/mbc.e05-03-0257.
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Transforming growth factor-β (TGFβ) signaling involves activation of a number of signaling pathways, several of which are controlled by phosphorylation events. Here, we describe a phosphoproteome profiling of MCF-7 human breast epithelial cells treated with TGFβ1. We identified 32 proteins that change their phosphorylation upon treatment with TGFβ1; 26 of these proteins are novel targets of TGFβ1. We show that Smad2 and Smad3 have different effects on the dynamics of TGFβ1-induced protein phosphorylation. The identified proteins belong to nine functional groups, e.g., proteins regulating RNA processing, cytoskeletal rearrangements, and proteasomal degradation. To evaluate the proteomics findings, we explored the functional importance of TGFβ1-dependent phosphorylation of one of the targets, i.e., transcription factor-II-I (TFII-I). We confirmed that TGFβ1 stimulated TFII-I phosphorylation at serine residues 371 and 743. Abrogation of the phosphorylation by replacement of Ser371 and Ser743 with alanine residues resulted in enhanced complex formation between TFII-I and Smad3, and enhanced cooperation between TFII-I and Smad3 in transcriptional regulation, as evaluated by a microarray-based measurement of expression of endogenous cyclin D2, cyclin D3, and E2F2 genes, and by a luciferase reporter assay. Thus, TGFβ1-dependent phosphorylation of TFII-I may modulate TGFβ signaling at the transcriptional level.
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Jacko, AM, L. Nan, J. Wei, J. Zhao, and Y. Zhao. "ID: 107: MITOXANTRONE INHIBITS TGFβ1-INDUCED SIGNALING THROUGH PROMOTING TGFβ RECEPTOR II DEGRADATION." Journal of Investigative Medicine 64, no. 4 (March 22, 2016): 962.1–962. http://dx.doi.org/10.1136/jim-2016-000120.104.
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BackgroundThe transforming growth factor β1 (TGFβ1) signaling pathway and its downstream effects play a central role in the pathogenesis of pulmonary fibrosis. TGFβ induces the phosphorylation of transcriptional factors SMAD2 and SMAD3, thereby increasing the expression of smooth muscle actin (SMA) and fibronectin (FN), two key proteins in the development of fibrosis. This effect is mediated by two receptors, TGFβ receptor I (TβRI) and TGFβ receptor II (TβRII). The protein stability of TβRI has been well studied, while the molecular regulation of TβRII still remains unclear. This project elucidates the role that Mitoxantrone (MTX), a FDA-approved anti-cancer drug, has in the regulation of TGFβ1 signaling through the reduction of TβRII stability.Methods and ResultsTo study TGFβ1 signaling, human fetal lung fibroblast cell line (MRC-5) was used. As expected, TGFβ1 treatment of MRC-5 cells induced phosphorylation of SMAD2 and SMAD3, with the ultimate expression of FN and SMA. These effects of TGFβ1 on FN and SMA were attenuated by MTX treatment, without altering SMAD2 and SMAD3 levels. To investigate the molecular mechanisms by which MTX regulates TGFβ1 signaling, we examined the expression of TβRI and TβRII. MTX reduced TβRII levels in time and dose dependent manners, while MTX had no effect on TβRI levels. MTX-induced TβRII degradation was inhibited by proteasome inhibitor (MG-132), not lysosome inhibitor (Leupeptin). Overexpression of HA tagged ubiquitin promoted MTX-induced TβRII degradation, suggesting that TβRII degradation by MTX is through the ubiquitin-proteasome pathway. Further, MTX increased TβRII ubiquitination and reduced TβRII neddylation, which has been known to negatively regulate TβRII stability by c-Cbl.ConclusionThese studies reveal that treatment with MTX reduces the levels of TβRII by increasing its ubiquitination and reduction of TβRII neddylation; therefore, MTX is a potential anti-fibrotic drug for the treatment of pulmonary fibrosis.The study is supported by NIH R01 HL112791 (to YZ), NIH R01GM115389 (to JZ), and American Lung Association Biomedical Research Grant RG350146 (to J.Z.).
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Gah, Asma, Mir S. Adil, Harika Sabbineni, Arti Verma, and Payaningal R. Somanath. "Differential regulation of TGFβ type-I receptor expressions in TGFβ1-induced myofibroblast differentiation." Canadian Journal of Physiology and Pharmacology 98, no. 12 (December 2020): 841–48. http://dx.doi.org/10.1139/cjpp-2020-0123.
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Fibroblast-to-myofibroblast (FibroMF) differentiation is crucial for embryogenesis and organ fibrosis. Although transforming growth factor-β (TGFβ) is the primary mediator of FibroMF differentiation, the type-I receptor (TGFβRI) responsible for this has not yet been confirmed. In the current study, we investigated the ALK1 and ALK5 expressions in TGFβ1-stimulated NIH 3T3 fibroblasts to compare with the data from the Gene Expression Omnibus (GEO) repository. In our results, whereas TGFβ1 treatment promoted FibroMF differentiation accompanied by increased ALK5 expression and reduced ALK1 expression, TGFβ1-induced FibroMF differentiation and increased α-smooth muscle actin (αSMA) and ALK5 expression were inhibited by co-treatment with ALK5 inhibitor SB431542. GEO database analysis indicated increased ALK5 expression and reduced ALK1 expression in fibrotic compared to normal mouse or human tissues correlating with organ fibrosis progression. Finally, the inhibitors of Akt, mTOR, and β-catenin suppressed TGFβ1-induced ALK5 expression, indicating that the Akt pathway promotes FibroMF differentiation via ALK5 expression and fibrosis.
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Suragani, Rajasekhar NVS, Pedro A. Martinez, Sharon M. Cawley, Robert Li, Robert Scott Pearsall, and Ravindra Kumar. "TGFb1 Antagonist Inhibits Fibrosis in a Murine Model of Myelofibrosis." Blood 126, no. 23 (December 3, 2015): 605. http://dx.doi.org/10.1182/blood.v126.23.605.605.
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Abstract Introduction: Myelofibrosis (MF) is a clonal stem cell disorder that originates from acquired mutations in the hematopoietic stem cells leading to abnormal kinase signaling, cell proliferation, cytokine expression, and splenomegaly and ultimately bone marrow (BM) fibrosis. Primary myelofibrosis (PMF), post-polycythemia vera (PV) MF and post-essential thrombocythemia MF are categorized under MF with overlapping disease phenotypes including progression to BM fibrosis. A genetic mutation in Janus kinase 2 (V617F) was identified as causative in ~95% PV, and ~50% of ET and PMF patients. Currently, treatment of MF patients with a JAK2 inhibitor offers symptomatic benefit, but does not alter the natural history of the disease or improve BM fibrosis. It is known that TGFβ1 is a critical regulator of fibrosis in many disease states. Elevated TGFβ1 levels were reported to be important for fibrosis in patients with MF. We hypothesize that inhibition of TGFβ1 signaling may prevent fibrosis and help reduce secondary morbidities associated with disease in MF patients. Therefore, we evaluated this hypothesis using a TGFβ1 antagonist in a murine model of MF. Methods: Transgenic JAK2 (V617F) mutant mice (MF model) and age-matched wild-type controls were used in the studies. Mice were dosed twice weekly with TGFβ1 antagonist (10 mg/kg). Complete blood counts (CBC), serum TGFβ1, bone metabolism and inflammatory cytokines levels were determined at different ages (2-12 months) during disease progression. Bone marrow and spleen cells were analyzed for different cell lineages by flow cytometry. Tissue sections were stained with H&E and reticulin to determine cellularity or degree of fibrosis respectively. Results: To understand the onset and progression of MF disease in JAK2 (V617F) mice, we initially analyzed the CBC and degree of fibrosis at various ages (2, 3, 4, 5, 8, 10 and 12 months) and compared the data with wild-type mice. These data were then correlated with the levels of TGFβ1 and other cytokines. As expected, red blood cells (RBC) and platelets were elevated in JAK2 mutant mice at all ages compared to wild-type mice, although a trend towards a progressive increase was observed between 2 to 5 months followed by a decrease from 8 to 14 months. Bone marrow fibrosis was detected starting at 5 months and worsened with age. JAK2 mutant mice displayed splenomegaly that increased as the disease progressed. Interestingly, serum levels of TGFβ1, TGFβ3 and bone metabolism cytokines (OPG, OPN, aFGF and Trance) displayed an increase at earlier ages (2-5 months) compared to the latter ages, a trend similar to RBC levels. These levels peaked during the initiation of fibrosis at 5 months. In contrast, inflammatory cytokines (such as IL6, IL-1β, and TNFα) were elevated at later ages consistent with disease progression. We initiated treatment with TGFβ1 antagonist in JAK2 (V617F) mice (N=8/treatment group) at 4 months of age, the age corresponding to elevated serum TGFβ1 levels and prior to the onset of fibrosis (at 5 months of age). Following 6 months of treatment, vehicle (VEH) treated JAK2 mutant mice displayed elevated RBC (+37.1%, P<0.001), platelets (+74.5%, P<0.001) and spleen weights (+9.5 fold, P<0.001) compared to wild-type mice. BM and spleen sections from VEH treated JAK2 mutant mice revealed severe fibrosis. TGFβ1 antagonist treatment of JAK2 mice displayed moderate effect on RBC (-8.4%, N.S) without any effect on platelet counts compared to VEH treatment. Flow-cytometry identified a reduced proportion of Ter119+ erythroid precursors in BM and spleen (-15%, P<0.05) and no change in CD41+ megakaryocytes. TGFβ1 antagonist treated mice displayed reduced spleen weights (-29%, P<0.01), and marked reduction in fibrosis in bone marrow (Figure) and spleen sections compared to VEH. Consistent with the reduction in fibrosis, TGFβ1 antagonist treated JAK2 mice displayed reduced IL-6 levels (-48.9%, P<0.05) compared to VEH treatment. Conclusion: Together, these data demonstrated that TGFβ1 levels were correlated with bone marrow fibrosis in a murine model of MF disease, and its inhibition using TGFβ antagonist reduces fibrosis, splenomegaly and inflammation in this murine model of myelofibrosis. Figure 1. Figure 1. Disclosures Suragani: Acceleron Pharma Inc: Employment, Equity Ownership, Patents & Royalties: No royalties. Martinez:Acceleron Pharma: Employment. Cawley:Acceleron Pharma Inc: Employment. Li:Acceleron Pharma: Employment, Equity Ownership. Pearsall:Acceleron Pharma Inc: Employment, Equity Ownership, Patents & Royalties. Kumar:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties.
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Zhang, Lei, Eiji Sato, Kenichi Amagasaki, Atsuhito Nakao, and Hirofumi Naganuma. "Participation of an abnormality in the transforming growth factor–β signaling pathway in resistance of malignant glioma cells to growth inhibition induced by that factor." Journal of Neurosurgery 105, no. 1 (July 2006): 119–28. http://dx.doi.org/10.3171/jns.2006.105.1.119.
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Object Malignant glioma cells secrete and activate transforming growth factor–β (TGFβ) and are resistant to growth inhibition by that factor. Nevertheless, the mechanism underlying this effect remains poorly understood. In this study, the mechanism of the resistance to growth inhibition induced by TGFβ was investigated. Methods The authors examined the expression of downstream components of the TGFβ receptor, including Smad2, Smad3, Smad4, and Smad7, and the effect of TGFβ1 treatment on the phosphorylation of Smad2 and the nuclear translocation of Smad2 and Smad3 by using 10 glioma cell lines and the A549 cell line, which is sensitive to TGFβ-mediated growth inhibition. The expression of two transcriptional corepressor proteins, SnoN and Ski, and the effect of TGFβ1 treatment on the expression of the SnoN protein and the cell cycle regulators p21, p15, cyclin-dependent kinase–4 (CDK4), and cyclin D1 were also examined. Expression of the Smad2 and Smad3 proteins was lower in the glioma cell lines than in the A549 cell line and in normal astrocytes. In particular, Smad3 expression was low or very low in nine of the 10 malignant glioma cell lines. Expression of Smad4 was low in four glioma cell lines, and expression of the Smad7 protein was similar when compared with protein expression in the A549 cell line and in normal astrocytes. The levels of Smad2 phosphorylation after TGFβ1 treatment were lower in glioma cell lines than in the A549 cell line, except for one glioma cell line. Seven of the 10 glioma cell lines exhibited lower levels of nuclear translocation of Smad2 and Smad3, and two cell lines that expressed very low levels of Smad3 protein showed no nuclear translocation. All glioma cell lines expressed the SnoN protein and its expression was unaltered by treatment with TGFβ1. Three glioma cell lines expressed high levels of the Ski protein. The expression of the p21cip1, p15INK4B, CDK4, and cyclin D1 proteins was not altered by TGFβ1 treatment, except in one cell line that displayed a slight increase in p21 protein. Overall, the expression of the Smad2 and Smad3 proteins was low in the glioma cell lines, the phosphorylation and nuclear translocation of Smad2 and Smad3 were impaired, and the TGFβ receptor signal did not affect the expression of the SnoN, p21, p15, cyclin D1, and CDK4 proteins. Conclusions These results suggest that the ability to resist TGFβ-mediated growth inhibition in malignant glioma cells is due to abnormalities in the TGFβ signaling pathway.
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Zhou, Xin, Junhong Li, Ludvig J. Backman, and Patrik Danielson. "Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk." International Journal of Molecular Sciences 23, no. 19 (September 21, 2022): 11073. http://dx.doi.org/10.3390/ijms231911073.
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Interleukin-1 (IL-1) and transforming growth factor-beta (TGFβ) are important cytokines involved in corneal wound healing. Here, we studied the effect of these cytokines on corneal stromal cell (keratocyte) differentiation. IL-1β treatment resulted in reduced keratocyte phenotype, as evident by morphological changes and decreased expression of keratocyte markers, including keratocan, lumican, ALDH3A1, and CD34. TGFβ1 treatment induced keratocyte differentiation towards the myofibroblast phenotype. This was inhibited by simultaneous treatment with IL-1β, as seen by inhibition of α-SMA expression, morphological changes, and reduced contractibility. We found that the mechanism of crosstalk between IL-1β and TGFβ1 occurred via regulation of the NF-κB signaling pathway, since the IL-1β induced inhibition of TGFβ1 stimulated keratocyte-myofibroblast differentiation was abolished by a specific NF-κB inhibitor, TPCA-1. We further found that Smad7 participated in the downstream signaling. Smad7 expression level was negatively regulated by IL-1β and positively regulated by TGFβ1. TPCA-1 treatment led to an overall upregulation of Smad7 at mRNA and protein level, suggesting that NF-κB signaling downregulates Smad7 expression levels in keratocytes. All in all, we propose that regulation of cell differentiation from keratocyte to fibroblast, and eventually myofibroblast, is closely related to the opposing effects of IL-1β and TGFβ1, and that the mechanism of this is governed by the crosstalk of NF-κB signaling.
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Guo, Hao, Lien Lu, Rijian Wang, Hayat Abdulkerim, Keith Reimann, Angus Thomson, and Mohamed Ezzelarab. "Impact of human mutant TGF-β1/Fc protein on memory and regulatory CD4+T cells following lymphodepletion in rhesus monkeys (THER2P.953)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 67.4. http://dx.doi.org/10.4049/jimmunol.194.supp.67.4.
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Abstract Transforming growth factor beta (TGFβ) is critical for regulatory T cells (Treg) homeostasis and regulation of peripheral tolerance. In rodents, combined human TGFβ1 fusion protein (TGFβ1/Fc) and rapamycin treatment prevents allograft rejection. We evaluated the influence of human TGFβ1/Fc on CD4+T cells in vitro, and in vivo following lymphodepletion in rhesus monkeys. In vitro, TGFβ1/Fc and rapamycin synergistically reduced ki67 expression and proliferation of rhesus memory T cells (Tmem), following CD3/CD28 activation or allo-stimulation. However, increased percentage of Treg and Treg/Th17 ratio were only observed in the presence of interleukin-2 (IL-2). Four monkeys received immunosuppression in the form of Thymoglobulin and rapamycin, without (n=2) or with (n=2) TGFβ1/Fc infusion. In monkeys receiving TGFβ1/Fc, trough levels were maintained at 2-7 ug/mL, and were undetectable by day-45. With no TGFβ1/Fc infusion, rapid recovery of Tmem to pre-depletion levels was observed by day-21, and continued to increase. In contrast, with TGFβ1/Fc infusion, the recovery of Tmem was delayed until day-56. In addition, increased Treg and Treg/Tmem ratio were observed in peripheral blood and lymph nodes. However, Treg/Th17 ratios were reduced in all monkeys. In lymphodepleted monkeys, infusion of human TGFβ1/Fc delays CD4+Tmem recovery, and is associated with increased Treg/Tmem ratio. Combined IL-2 and TGFβ1/Fc infusion may be essential to improve Treg/Th17 ratio after lymphodepletion.
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Maharjan, Babu Raja, Susan V. McLennan, Stephen M. Twigg, and Paul F. Williams. "The Effect of TGFβ1 in Adipocyte on Inflammatory and Fibrotic Markers at Different Stages of Adipocyte Differentiation." Pathophysiology 29, no. 4 (November 23, 2022): 640–49. http://dx.doi.org/10.3390/pathophysiology29040050.
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Transforming growth factor beta (TGFβ) is a versatile cytokine. Although a profibrotic role of TGFβ is well established, its effect on tissue inhibitor of metalloproteinase (TIMPs) and inflammatory mediators are incompletely described. This study investigates the profibrotic and pro-inflammatory role of TGFβ1 during adipocyte differentiation. NIH3T3L1 cells were used for the in vitro study and were differentiated by adding a standard differentiation mix either with rosiglitazone (R-Diff) or without (S-Diff). Recombinant TGFβ1 (2 ng/mL) was added to the undifferentiated preadipocyte during the commitment stage and at the terminal differentiation stage. TGFβ1 treatment significantly decreased adiponectin mRNA at both early commitment (>300 fold) and terminal differentiated cells [S-Diff (~33%) or R-Diff (~20%)]. TGFβ1 upregulated collagen VI mRNA and its regulators connective tissue growth factor (CCN2/CTGF), TIMP1 and TIMP3 mRNA levels in undifferentiated preadipocytes and adipocytes at commitment stage. But in the terminal differentiated adipocytes, changes in mRNA and protein of collagen VI and TIMP3 mRNA were not observed despite an increase in CCN2/CTGF, TIMP1 mRNA. Although TGFβ1 upregulated interleukin-6 (IL6) and monocyte chemoattractant protein-1 (MCP1) mRNA at all stages of differentiation, decreased tumor necrosis factor-α (TNFα) mRNA was observed early in adipocyte differentiation. This study highlights the complex role of TGFβ1 on extracellular matrix (ECM) remodeling and inflammatory markers in stimulating both synthetic and inhibitory markers of fibrosis at different stages of adipocyte differentiation.
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Iqbal, Aqsa, Ulrike May, Stuart N. Prince, Tero A. H. Järvinen, and Ahlke Heydemann. "Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology." Pharmaceutics 13, no. 9 (September 18, 2021): 1506. http://dx.doi.org/10.3390/pharmaceutics13091506.
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Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy.
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Di Bartolo, Daniel, and Ethel Cesarman. "Inhibition of the TGFβ Pathway in Primary Effusion Lymphoma." Blood 108, no. 11 (November 16, 2006): 4352. http://dx.doi.org/10.1182/blood.v108.11.4352.4352.
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Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV) interferes with a number of cellular pathways involved in apoptosis and cell cycle regulation. Since TGFβ is a potent inducer of cell cycle arrest and apoptosis in hematopoietic lineages, we were interested in examining whether TGFβ signaling is blocked in primary effusion lymphoma (PEL) and if so whether KSHV plays a role in this repression. Treatment with TGFβ1 had no effect on either cell cycle or apoptosis in several PEL cell lines. The defect in this pathway was found to be a lack of the TGFβ type II receptor (TβRII), expression. Upon transfection of TβRII, PEL cell lines become responsive to TGFβ1 treatment. We are currently examining how TβRII transcription is regulated in PEL. The lack of TβRII expression in some tumors has been attributed to altered chromatin structure due to hypoacetylation. Treatment with both a demethylating agent and a histone deacetylase inhibitor resulted in expression of this receptor in PEL. Several KSHV latent gene products are known to interact with or recruit p300, a histone acetyltransferase, for other cellular processes. It is possible that the interaction of one or more of these viral gene products with p300 may serve to prevent it from acetylating histones associated with the TβRII gene and thereby repress its transcription. We have also found by ELISA that PEL cells secrete a higher level of TGFβ1 than other TGF β responsive B cell lines. Increased secretion of TGFβ1 in conjunction with downregulation of TβRII may be a mechanism by which KSHV creates an immunosuppressed environment while allowing infected cells to grow free from the constraints of this pathway.
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Mengyao, Liu. "The Role of Matrix Metalloproteinase-13 (MMP13) in TGFβ/BMP Pathway Regulation of Fibro-Adipogenic Progenitor (FAP) Differentiation." Cellular Physiology and Biochemistry 56, no. 6 (December 20, 2022): 730–43. http://dx.doi.org/10.33594/000000596.
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Background/Aims: Muscle fibrosis and fatty infiltration (FI) are common complications seen in various muscle disease states. Recent studies indicate that muscle residential fibro/adipogenic progenitors (FAPs) are the major cellular source for muscle fibrosis and FI. We previously showed that MMP13 knockout (KO) mice have significantly increased FI, suggesting an important role of MMP13 in muscle FI. However, how MMP13 affects the differentiation of FAPs remains unknown. Methods: In order to assess the role of MMP-13 on FAP differentiation, we isolated FAPs from wildtype C57BL/6 and MMP13 knock out mice with FACS using CD31-, CD45-, Integrin α7- and Sca-1+ markers. FAPs were cultured in 24 well plate after FACS.in standard media till 80% confluent and then switched to adipogenic medium. In order to study the role of TGFβ and BMP in their differentiation, FAPs from both wildtype and MMP13 KO mice were treated with TGFβ1 (5 ng/ml). For MMP13 inhibitor treatment, FAPs from wildtype mice were incubated in adipogenic medium containing 10 µM MMP13 inhibitor (or vehicle) for 2 weeks. Immunofluorescence and gene expression analysis were used to assess FAP adipogenic and fibrogenic differentiation. FAPs were stained with Perilipin A (FITC, adipogenesis marker) and αSMA (Red, fibroblast marker), and DAPI. Real time PCR was performed for gene expression evaluation. A two-tailed Anova was used for statistical comparisons between groups, with p ≤ 0.05. Data are presented as mean ± standard deviation. Results: In this study, we isolated FAPs from wildtype C57BL/6 and MMP13 KO mice and evaluated their adipogenic and fibrogenic differentiation in vitro . MMP13 KO FAPs demonstrated enhanced adipogenesis but reduced fibrogenesis compared to wildtype FAPs. Treating wildtype FAPs with an MMP13 inhibitor simulated phenotypes seen in MMP13 KO FAPs. In order to assess the role of MMP13 on TGFβ/BMP signaling in regulating FAP differentiation, we treated wildtype and MMP13 KO FAPs with TGFβ1, BMP7, TGFβ inhibitor, and BMP inhibitor. TGFβ1 treatment significantly enhanced fibrogenesis, but inhibited adipogenesis of wildtype FAPs. However, treatment with BMP7 showed the opposite effect. Interestingly, the effect of TGFβ1/BMP7 was voided in MMP13 KO FAPs. Treating wildtype FAPs with MMP13 inhibitor also abolished the effect of TGFβ1/BMP7 in FAP differentiation. Conclusion: Results from this study showed that TGFβ1 inhibits FAP adipogenesis but stimulates FAP fibrogenesis. BMP7 was shown to promote FAP adipogenesis but reduce its fibrogenesis. The role of the TGFβ/BMP signaling pathway regulating FAP differentiation was found to be MMP13 dependent. This study suggests that MMP13 is a critical downstream effector in TGFβ/BMP pathway which may serve as a new therapeutic target for muscle fibrosis and FI.
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Yuan, Shuanghu, Jinming Yu, Xuwei Cai, and Feng-Ming (Spring) Kong. "The association of plasma TGFβ1 during radiotherapy and genotypes of TGFβ1 pathway in patients with non-small cell lung cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e21115-e21115. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e21115.
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e21115 Background: Radiation induced thoracic toxicities (RITT) in lung, esophagus and pericardium are dose-limited toxicities in patients with non-small cell lung cancer (NSCLC). Plasma transforming growth factor-beta1 (TGFβ1) and its change during radiotherapy was reported as a biomarker and single nucleotide polymorphisms (SNP) in TGFβ1 pathway was associated with RITT in our previous studies. In order to explore the mechanism of RITT, we tested whether plasma TGFβ1 was associated with genotypes of TGFβ1, tissue plasminogen activator (tPA) and angiotensin converting enzyme (ACE). Methods: Patients with stage I-III NSCLC enrolled in prospective clinical trials were eligible. All patients received radiotherapy with or without concurrent chemotherapy. Platelet-poor plasma was obtained pre-RT and at 4–5 weeks (40–50 Gy) during RT. Plasma TGF-β1 was measured using an enzyme-linked immunosorbent assay. The DNA samples extracted from blood before treatment were analyzed for the following genetic variations: TGFβ1 509C/T, TPA -7351 C/T, and ACE I/D. Results: 76 NSCLC patients received definitive radiotherapy (median dose 66 Gy) were enrolled. For the entire group of patients, the mean pre-RT TGFß1 level was 10.7±2.3 ng/ml, and the mean during-RT TGFß1 level was 6.0±0.7 ng/ml. No significant TGFß1 level differences were found at pre-RT and during-RT in patients with different genotypes of TGFß1 and tPA. Only ACE DD group had marginally higher pre-RT TGFß1 level than II and ID group (DD 23.6ng/ml vs. II 9.0ng/ml vs. ID 7.5ng/ml, p = 0.05), but no difference at during-RT(p=0.346) or during-RT/pre-RT ratio(p = 0.433). However, patients with TGFß1 509CC had higher elevation of plasma TGF ß1 level at fourth week during-RT than T allele carriers (TGFß1 level ratio of during-RT/pre-RT were CC 1.4±0.2 vs. T allele carriers 0.7±0.1, p=0.047). Conclusions: This exploratory study demonstrated that patients with TGFß1 509CC had higher elevation of plasma TGF ß1 level at fourth week during-RT than T allele carriers. This can help explain the correlation of TGF ß1 level elevation and higher risk of radiation induced lung toxicity in patients with NSCLC.
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Lee, Mi-Sook, Tae Young Kim, Yong-Bae Kim, Sung-Yul Lee, Seong-Gyu Ko, Hyun-Soon Jong, Tae-You Kim, Yung-Jue Bang, and Jung Weon Lee. "The Signaling Network of Transforming Growth Factor β1, Protein Kinase Cδ, and Integrin Underlies the Spreading and Invasiveness of Gastric Carcinoma Cells." Molecular and Cellular Biology 25, no. 16 (August 15, 2005): 6921–36. http://dx.doi.org/10.1128/mcb.25.16.6921-6936.2005.
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ABSTRACT Integrin-mediated cell adhesion and spreading enables cells to respond to extracellular stimuli for cellular functions. Using a gastric carcinoma cell line that is usually round in adhesion, we explored the mechanisms underlying the cell spreading process, separate from adhesion, and the biological consequences of the process. The cells exhibited spreading behavior through the collaboration of integrin-extracellular matrix interaction with a Smad-mediated transforming growth factor β1 (TGFβ1) pathway that is mediated by protein kinase Cδ (PKCδ). TGFβ1 treatment of the cells replated on extracellular matrix caused the expression and phosphorylation of PKCδ, which is required for expression and activation of integrins. Increased expression of integrins α2 and α3 correlated with the spreading, functioning in activation of focal adhesion molecules. Smad3, but not Smad2, overexpression enhanced the TGFβ1 effects. Furthermore, TGFβ1 treatment and PKCδ activity were required for increased motility on fibronectin and invasion through matrigel, indicating their correlation with the spreading behavior. Altogether, this study clearly evidenced that the signaling network, involving the Smad-dependent TGFβ pathway, PKCδ expression and phosphorylation, and integrin expression and activation, regulates cell spreading, motility, and invasion of the SNU16mAd gastric carcinoma cell variant.
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Petiti, Juan Pablo, Liliana del Valle Sosa, María Eugenia Sabatino, Alicia Maldré Vaca, Silvina Gutiérrez, Ana Lucía De Paul, and Alicia Inés Torres. "Involvement of MEK/ERK1/2 and PI3K/Akt Pathways in the Refractory Behavior of GH3B6 Pituitary Tumor Cells to the Inhibitory Effect of TGFβ1." Endocrinology 156, no. 2 (November 13, 2014): 534–47. http://dx.doi.org/10.1210/en.2014-1070.
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Pituitary tumor cells have a poor response to the growth inhibitory effect of TGFβ1, possibly resulting from the cross talk of TGFβ/Smads signal with other signaling pathways, an undescribed mechanism in these tumoral cells. To address this hypothesis, we investigated whether the mitogen-activated extracellular signal-regulated kinase (MEK)/ERK1/2 and phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) pathways were able to regulate the antimitogenic effect of TGFβ1 on GH3B6 cells. TGFβ1 treatment decreased the cell proliferation and induced an activation of mothers against decapentaplegic homolog 2/3 (Smad2/3), effects that were potentiated by MEK and PI3K inhibitors, thus indicating the existence of a cross talk between TGFβ1/Smad with the MEK/ERK1/2 or PI3K/Akt pathways. In addition, through immunoprecipitation assays, a direct interaction was observed between Smad2/3-ERK1/2 and Smad2/3-Akt, which decreased when the GH3B6 cells were incubated with TGFβ1 in the presence of MEK or PI3K inhibitors, thereby suggesting that the ERK1/2- and Akt-activated states were involved. These Smad2/3-ERK1/2 and Smad2/3-Akt associations were also confirmed by confocal and transmission electron microscopy. These findings indicate that the TGFβ1-antimitogenic effect in GH3B6 cells was attenuated by the MEK/ERK1/2 and PI3K/Akt pathways via modulating Smad2/3 phosphorylation. This molecular mechanism could explain in part the refractory behavior of pituitary tumor cells to the inhibitory effect of TGFβ1.
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Hong, Liu, Yasuhiko Tabata, Susumu Miyamoto, Masaya Yamamoto, Keisuke Yamada, Nobuo Hashimoto, and Yoshito Ikada. "Bone regeneration at rabbit skull defects treated with transforming growth factor—β1 incorporated into hydrogels with different levels of biodegradability." Journal of Neurosurgery 92, no. 2 (February 2000): 315–25. http://dx.doi.org/10.3171/jns.2000.92.2.0315.
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Object. Skull bone regeneration induced by transforming growth factor—β1 (TGFβ1)—containing gelatin hydrogels (TGFβ1-hydrogels) was investigated using a rabbit skull defect model. Different strengths of TGFβ1 were examined and compared: different TGFβ1 doses in gelatin hydrogels with a fixed water content, different water contents in gelatin hydrogels with a fixed TGFβ1 dose, and TGFβ1 in solution form. In addition, regenerated skull bone was observed over long time periods after treatment.Methods. Soft x-ray, dual energy x-ray absorptometry, and histological studies were performed to assess the time course of bone regeneration at a 6-mm-diameter skull defect in rabbits after treatment with TGFβ1-hydrogels or other agents. The influence of TGFβ1 dose and hydrogel water content on skull bone regeneration by TGFβ1-hydrogels was evaluated. Gelatin hydrogels with a water content of 95 wt% that incorporated at least 0.1 µg of TGFβ1 induced significant bone regeneration at the rabbit skull defect site 6 weeks after treatment, whereas TGFβ1 in solution form was ineffective, regardless of dose. The in vivo degradability of the hydrogels, which varied according to water content, played an important role in skull bone regeneration induced by TGFβ1-hydrogels. In our hydrogel system, TGFβ1 is released from hydrogels as a result of hydrogel degradation. When the hydrogel degrades too quickly, it does not retain TGFβ1 or prevent ingrowth of soft tissues at the skull defect site and does not induce bone regeneration at the skull defect. It is likely that hydrogel that degrades too slowly physically impedes formation of new bone at the skull defect. Following treatment with 0.1-µg TGFβ1-hydrogel (95 wt%), newly formed bone remained at the defect site without being resorbed 6 and 12 months later. The histological structure of the newly formed bone was similar to that of normal skull bone. Overgrowth of regenerated bone and tissue reaction were not observed after treatment with TGFβ1-hydrogels.Conclusions. A TGFβ1-hydrogel with appropriate biodegradability will function not only as a release matrix for the TGFβ1, but also as a space provider for bone regeneration. The TGFβ1-hydrogel is a promising surgical tool for skull defect repair and skull base reconstruction.
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Wei, J., AM Jacko, L. Nan, J. Zhao, J. Tan, DJ Kass, and Y. Zhao. "ID: 108: DEUBIQUITINATING ENZYME 11 STABILIZES TGFβ RECEPTOR II AND REGULATES TGFβ1 SIGNALING IN PULMONARY FIBROBLAST." Journal of Investigative Medicine 64, no. 4 (March 22, 2016): 962.2–963. http://dx.doi.org/10.1136/jim-2016-000120.105.
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BackgroundProtein stability is regulated by ubiquitination and deubiquitination. The ubiquitin-deubiquitination system contributes to the regulation of tumor growth factor β1 (TGFβ1) signaling. TGFβ1 mediates its signaling and pro-fibrotic effects through binding to its receptors, TGFβ receptor I (TβRI) and TβRII. Here we reveal that deubiquitinating enzyme USP11 regulates TGFβ1 signaling through stabilization of TβRII.Methods and ResultsBleomycin-induced pulmonary fibrosis is a wildly used murine model of pulmonary fibrosis. Analysis of murine lung tissue lysates from 3 weeks of bleomycin challenge revealed that USP11 levels were elevated in lung tissues from bleomycin-challenged mice. TGFβ1 plays a critical role in the pathogenesis of pulmonary fibrosis. TGFβ1 treatment of human lung fibroblast cells (HLF) induced tyrosine phosphorylation of USP11. To investigate the effect of USP11 in the TGFβ1 signaling, HLF cells were transfected with USP11 shRNA. USP11 shRNA reduced USP11 levels as well as TβRII expression in HLF. Overexpression of HA tagged USP11 (USP11-HA) enhanced TβRII lifespan. Co-immunostaining revealed that V5 tagged TβRII (TβRII-V5) and USP11-HA colocalized at plasma membrane and cytoplasm. TβRII ubiquitination was promoted by USP11 shRNA, while it was reduced by USP11-HA. Further, we investigated the role of USP11 in TGFβ1-mediated signaling, such as phosphorylation of SMAD2 and SMAD3. USP11-HA facilitated TGFβ1-induced phosphorylation of SMAD2 and SMAD3, which was attenuated in USP11 shRNA transfected HLF cells.ConclusionThis study indicates that USP11 contributes to the pathogenesis of pulmonary fibrosis by regulating targeting TβRII for its deubiquitination and stabilization.This work was supported by the National Institutes of Health (R01HL091916 and R01HL112791 to Y.Z, R01GM115389 to J.Z.), American Heart Association 12SDG9050005 (J.Z.), American Lung Association Biomedical Research Grant RG350146 (J.Z.).
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Nam, Bora, Hyosun Park, Young Lim Lee, Younseo Oh, Jinsung Park, So Yeon Kim, Subin Weon, et al. "TGFβ1 Suppressed Matrix Mineralization of Osteoblasts Differentiation by Regulating SMURF1–C/EBPβ–DKK1 Axis." International Journal of Molecular Sciences 21, no. 24 (December 21, 2020): 9771. http://dx.doi.org/10.3390/ijms21249771.
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Transforming growth factor β1 (TGFβ1) is a major mediator in the modulation of osteoblast differentiation. However, the underlying molecular mechanism is still not fully understood. Here, we show that TGFβ1 has a dual stage-dependent role in osteoblast differentiation; TGFβ1 induced matrix maturation but inhibited matrix mineralization. We discovered the underlying mechanism of the TGFβ1 inhibitory role in mineralization using human osteoprogenitors. In particular, the matrix mineralization-related genes of osteoblasts such as osteocalcin (OCN), Dickkopf 1 (DKK1), and CCAAT/enhancer-binding protein beta (C/EBPβ) were dramatically suppressed by TGFβ1 treatment. The suppressive effects of TGFβ1 were reversed with anti-TGFβ1 treatment. Mechanically, TGFβ1 decreased protein levels of C/EBPβ without changing mRNA levels and reduced both mRNA and protein levels of DKK1. The degradation of the C/EBPβ protein by TGFβ1 was dependent on the ubiquitin–proteasome pathway. TGFβ1 degraded the C/EBPβ protein by inducing the expression of the E3 ubiquitin ligase Smad ubiquitin regulatory factor 1 (SMURF1) at the transcript level, thereby reducing the C/EBPβ-DKK1 regulatory mechanism. Collectively, our findings suggest that TGFβ1 suppressed the matrix mineralization of osteoblast differentiation by regulating the SMURF1-C/EBPβ-DKK1 axis.
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T.A., Dronova,, Babyshkina, N.N., Slonimskaya, E.M., and Cherdyntseva, N.V. "FEATURES OF EXPRESSION OF TRANSFORMING GROWTH FACTOR BETA IN ESTROGEN-POSITIVE BREAST CANCER." CARDIOMETRY, no. 24 (November 30, 2022): 62. http://dx.doi.org/10.18137/cardiometry.2022.24.conf.33.
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Changes in the activity of growth factors and their receptors play a key role in shaping the response to treatment with anticancer hormonal drugs. The aim of this work was to study the relationship between the TGFβ1 and TGFβR1 expression and the progression of breast cancer (BC) during tamoxifen therapy.
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Danforth, D. N. "All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor β to stimulate apoptosis in MCF-7 breast cancer cells." Journal of Endocrinology 183, no. 2 (November 2004): 395–404. http://dx.doi.org/10.1677/joe.1.05497.
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The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throughout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis. The negative growth factor-transforming growth factor β (TGFβ) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGFβ1 secretion over 72 h. TGFβ1 alone had no apoptotic effects on these cells; however, TGFβ1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGFβ1+AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGFβ antibody did not block down-regulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGFβ, although TGFβ may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.
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Mascarenhas, John, Heidi E. Kosiorek, Lilian Varricchio, Rupali Bhave, Andrew T. Kuykendall, Rami Komrokji, Aaron T. Gerds, et al. "Rationale for and Results of a Phase I Study of the TGF-β 1/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial." Blood 136, Supplement 1 (November 5, 2020): 6–8. http://dx.doi.org/10.1182/blood-2020-140830.
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Preclinical Rationale: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm for which there are limited therapies. TGFβ plays a pivotal role in the pathobiology of MF by not only promoting bone marrow fibrosis (BMF) and collagen deposition, but also by enhancing the dormancy of normal but not MF hematopoietic stem cells (HSCs). TGFβ has also previously been reported to inhibit normal megakaryocyte (MK) production (Bruno et al Blood 1998). TGFβ1 promotes the synthesis of collagen by normal human mesenchymal stromal cells (MSCs) and activates the TGFβ receptor I/SMAD pathway as well as non-canonical TGFβ pathways. We generated MKs from MF subject mononuclear cells (MNCs) and showed that they elaborated significantly greater levels of TGFβ1 than TGFβ2/3 TGFβ1 treatment reduced the numbers of hematopoietic colonies generated by normal but not MF MNCs. Treatment of MSCs with AVID200, a potent TGFβ1/3 protein trap, significantly decreased MSC proliferation, phosphorylation of SMAD2, and collagen expression. Robust expression of pSMAD2 was observed in the absence of exogenous TGFβ in normal donor or MF-MKs, Addition of AVID200 to -MKs decreased pSMAD2 without affecting total SMAD2/3, indicating that AVID200 blocks the effects of autocrine TGFβ produced by MKs and led to increased numbers of MKs. Moreover, treatment of primary MF MNCs with AVID200 led to increased numbers of progenitor cells with wild type JAK2 and a reduction of mutated colonies. AVID200 blocked TGFβ1-induced p57Kip2 expression and SMAD2 activation by MF MNCs allowing the normal progenitor cells to preferentially cycle, proliferate, and form hematopoietic colonies. Clinical Trial Design: Based on these findings, a phase 1 trial of AVID200 is ongoing in INT-2/high risk MF subjects resistant or intolerant to ruxolitinib; baseline platelet count of ≥ 25 x 109/L, and grade 2/3 BMF. Subjects received intravenous AVID200 (Lots A and B) in dose cohorts of 180 mg/m2 (A), 550 mg/m2 (A), 180 mg/m2 (B) on Day 1 of a 21 day cycle. Cohorts of 3 subjects with a target toxicity rate of 30% were enrolled to estimate the maximum tolerated dose (MTD). A modified toxicity probability interval design was used. Response was assessed by IWG/ELN criteria after 6 cycles of AVID200. Subjects attaining at least a CI or SD with a decrease in BMF by ≥1 grade, continued AVID200. Clinical Trial Results: 10 subjects were enrolled (1 withdrew before receiving treatment) and 9 were treated with AVID200 and were evaluable for DLT assessment [Table1]. Median time after ruxolitinib discontinuation was 3.5 months (0.5-12.2). No DLTs were observed. Grade 3/4 AEs (regardless of attribution) were observed in 6 (66.7%) subjects. Grade 3/4 non-hematologic AEs observed were epistaxis (1, 11.1%), extraocular muscle paresis (1, 11.1%), fatigue (1, 11.1%) and rash (1, 11.1%). Grade 3/4 hematologic AEs were anemia (3, 33.3%) and thrombocytopenia (2, 22.2%) [Table 2]. The median number of cycles received was 5.7 (range 0 - 12). 5 subjects received 6+ cycles and were evaluable. CI occurred in 2 subjects [anemia, spleen and TSS (n=1); TSS (n=1)] 1 of which is still being treated, 2 subjects had SD, 1 subject with 21% blasts prior to study treatment had progressive MPN-BP. 4 subjects failed to reach response evaluation after 6 cycles, 2 had PD due to increasing splenomegaly, 1 subject received an allogeneic transplant and 1 is still being treated [Cycle 2]. The median platelet count at baseline was 114 (range: 42-290) and 159 after cycle 6 [Figure 1]. Maximum changes in platelets from baseline was +64% [range -73%, 169%] in all subjects. 7 subjects had an increase in platelets from baseline during treatment. 2 subjects normalized their platelet count from thrombocytopenic levels. The effect of AVID200 on BMF is currently being examined. 2 subjects remain on treatment. Conclusions: AVID200 a TGFβ1/3 protein trap is well tolerated in advanced MF subjects. Clinical responses were observed at the 550 mg dose and the expansion efficacy cohorts at doses 2 and 3 are enrolling 12 additional subjects. Furthermore, AVID200 therapy improved thrombocytopenia in MF subjects which may be due to AVID200 inhibiting the effects of TGFβ1 on normal MKpoiesis. Updated subject safety and efficacy data along with correlative data will be presented. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Komrokji:Jazz: Honoraria, Speakers Bureau; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Geron: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria. Gerds:Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Incyte Corporation: Consultancy, Research Funding. Migliaccio:Novartis: Research Funding. O'Connor-McCourt:Forbius: Current Employment. Tremblay:Forius: Current Employment. Nadler:Forbius: Consultancy; Nadler Pharma Associates: Current Employment; Symphogen: Consultancy; Iksuda Therapeutics: Consultancy; Tessa Therapeutics: Consultancy. Mesa:Celgene: Research Funding; Genetech: Research Funding; Samus: Research Funding; Promedior: Research Funding; CTI: Research Funding; LaJolla Pharma: Consultancy; Incyte: Research Funding; Sierra Onc: Consultancy; Abbvie: Research Funding; Novartis: Consultancy. Hoffman:Forbius: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Protagonist: Consultancy.
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Phanish, Mysore K., Nadia A. Wahab, Paul Colville-Nash, Bruce M. Hendry, and Mark E. C. Dockrell. "The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFβ1 responses in human proximal-tubule epithelial cells." Biochemical Journal 393, no. 2 (December 23, 2005): 601–7. http://dx.doi.org/10.1042/bj20051106.
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In chronic renal diseases, progressive loss of renal function correlates with advancing tubulo-interstitial fibrosis. TGFβ1-Smad (transforming growth factor-β1–Sma and Mad protein) signalling plays an important role in the development of renal tubulo-interstitial fibrosis. Secretion of CTGF (connective-tissue growth factor; CCN2) by PTECs (proximal-tubule epithelial cells) and EMT (epithelial–mesenchymal transdifferentiation) of PTECs to myofibroblasts in response to TGFβ are critical Smad-dependent events in the development of tubulo-interstitial fibrosis. In the present study we have investigated the distinct contributions of Smad2 and Smad3 to expression of CTGF, E-cadherin, α-SMA (α-smooth-muscle actin) and MMP-2 (matrix-metalloproteinase-2) in response to TGFβ1 treatment in an in vitro culture model of HKC-8 (transformed human PTECs). RNA interference was used to achieve selective and specific knockdown of Smad2 and Smad3. Cellular E-cadherin, α-SMA as well as secreted CTGF and MMP-2 were assessed by Western immunoblotting. TGFβ1 treatment induced a fibrotic phenotype with increased expression of CTGF, MMP-2 and α-SMA, and decreased expression of E-cadherin. TGFβ1-induced increases in CTGF and decreases in E-cadherin expression were Smad3-dependent, whereas increases in MMP-2 expression were Smad2-dependent. Increases in α-SMA expression were dependent on both Smad2 and Smad3 and were abolished by combined knockdown of both Smad2 and Smad3. In conclusion, we have demonstrated distinct roles for Smad2 and Smad3 in TGFβ1-induced CTGF expression and markers of EMT in human PTECs. This can be of therapeutic value in designing targeted anti-fibrotic therapies for tubulo-interstitial fibrosis.
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Yap, Timothy A., Minal A. Barve, Justin F. Gainor, Colin D. Weekes, Bruno Bockorny, Yawen Ju, Ryan Faucette, et al. "First-in-human phase 1 trial (DRAGON) of SRK-181, a potential first-in-class selective latent TGFβ1 inhibitor, alone or in combination with anti-PD-(L)1 treatment in patients with advanced solid tumors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): TPS3146. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps3146.
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TPS3146 Background: Transforming growth factor-beta 1 (TGFβ1) is a key mediator of primary resistance to programmed cell death protein 1 (PD-1) pathway blockade. SRK-181 is a fully human, highly potent and selective monoclonal antibody that inhibits latent TGFβ1 activation. SRK-181 has minimal or no binding to latent TGFβ2 and TGFβ3 isoforms or to active TGFβ growth factors. In mouse tumor models (bladder, melanoma, and breast cancer), SRK-181 in combination with anti-PD1 therapy overcame primary anti-PD-1 resistance and showed survival benefit. No cardiotoxicities (valvulopathy) were observed with SRK-181 in 4-week GLP nonclinical toxicology studies. Thus, the potency and selectivity of SRK-181 may overcome PD-1 inhibitor resistance and toxicity of non-selective TGFβ pathway approaches. Methods: The DRAGON trial NCT04291079 is an ongoing multicenter, open-label, phase 1 study of SRK-181 administered by IV infusion every 3 weeks (Q3W) alone or in combination with anti-PD-(L)1 in patients (pts) with locally advanced or metastatic solid tumors. The study comprises 3 parts: Part A of the study follows a standard 3+3 dose escalation trial design to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of SRK-181 alone (Part A1) or in combination with the anti-PD-(L)1 agent that is approved for the respective tumor indication (Part A2). Part A1 and Part A2 will determine maximum tolerated dose (MTD) or maximum administered dose and Recommended Phase 2 Dose (RP2D) for Part B. Part B (expansion phase) will evaluate combination treatment of SRK-181 with anti-PD-(L)1 in pts with non-small cell lung cancer, urothelial carcinoma (UC), melanoma or other advanced solid tumors, to confirm the tolerability of the RP2D and to evaluate the antitumor activity of combination treatment. Pts in Part A2 and Part B must have previously received an anti-PD-(L)1 therapy approved in their tumor indication and considered non-responders (best response of stable disease or disease progression) to anti-PD-(L)1 monotherapy. Pts in Part B must have received the most recent dose of the prior anti-PD-(L)1 within 6 months of study enrollment (9 months for UC cohort). Safety, PK, PD and efficacy data will be collected and monitored throughout the study. Detailed translational PD and predictive biomarker studies for SRK-181 will include a novel digital pathology analysis of CD8 to assess the alteration of immune profile in tumor microenvironment and TGFb pathway biomarkers, such as quantitative analysis of tumor phospho-Smad2 and circulating levels of TGFb1 ligand. As of Feb 01 2021, dose escalation has proceeded to the highest planned dose of 2400 mg Q3W in Part A1 (monotherapy) and to 800 mg Q3W in Part A2 (anti-PD-(L)1 combination). Additional planned doses in Part A2 are 1600 mg and 2400 mg Q3W. Clinical trial information: NCT04291079.
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De, A., T. E. Morgan, R. C. Speth, N. Boyadjieva, and D. K. Sarkar. "Pituitary lactotrope expresses transforming growth factor β (TGFβ) type II receptor mRNA and protein and contains 125I-TGFβ1 binding sites." Journal of Endocrinology 149, no. 1 (April 1996): 19–27. http://dx.doi.org/10.1677/joe.0.1490019.
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Abstract Transforming growth factor β1 (TGFβ1) has recently been shown to be produced in the prolactin (PRL)-secreting lactotropes of the pituitary gland. TGFβ1 inhibits lactotropic secretion and proliferation, and the production of TGFβ1 in lactotropes is reduced during lactotropic growth following estrogen treatment in ovariectomized rats. In many estrogen-responsive tissues, TGFβ1 has been shown to exert its effect by binding to TGFβ1 type II receptors (TβR II) at the cell surface. In this study, we sought to ascertain whether TβR II is involved in TGFβ1 action on lactotropes by determining the changes of TβR II mRNA and protein levels and specific 125I-TGFβ1 binding sites on the lactotropes during estrogen-induced proliferation of lactotropes in Fischer 344 rats. Double immunohistochemical procedures were employed to identify immunoreactive TβR II in PRL-reactive cells. The majority of TβR II-reactive cells in the anterior pituitary were observed to be lactotropes. Dual immunohistochemistry and in situ hybridization procedures also indicated that lactotropes were the major cell types containing TβR II mRNA hybrids. Both the levels of immunoreactive TβR II protein and in situ TβR II mRNA hybrids in the pituitary were significantly decreased in ovariectomized rats after 15 days of estrogen treatment. Determination of 125I-TGFβ1 binding sites in lactotropes by double immunohistochemistry and receptor autoradiography also revealed specific binding sites of 125I-TGFβ1 in lactotropes in the anterior pituitary. 125I-TGFβ1 binding in the anterior pituitary was also reduced following estrogen treatment in ovariectomized rats. These data suggest that down-regulation of TβR II may be an important mechanism of estrogen action on lactotropic cell growth and PRL secretion, and further support the notion that TGFβ1 controls lactotropic function by autocrine/paracrine mechanisms. Journal of Endocrinology (1996) 149, 19–27
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Bendinelli, Paola, Paola Maroni, Valentina Dall’Olio, Emanuela Matteucci, and Maria Alfonsina Desiderio. "Bone Metastasis Phenotype and Growth Undergo Regulation by Micro-Environment Stimuli: Efficacy of Early Therapy with HGF or TGFβ1-Type I Receptor Blockade." International Journal of Molecular Sciences 20, no. 10 (May 22, 2019): 2520. http://dx.doi.org/10.3390/ijms20102520.
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Hepatocyte growth factor (HGF) and transforming growth factor β1 (TGFβ1) are biological stimuli of the micro-environment which affect bone metastasis phenotype through transcription factors, but their influence on the growth is scarcely known. In a xenograft model prepared with 1833 bone metastatic cells, derived from breast carcinoma cells, we evaluated mice survival and Twist and Snail expression and localization after competitive inhibition of HGF with NK4, or after blockade of TGFβ1-type I receptor (RI) with SB431542: in the latter condition HGF was also measured. To explain the in vivo data, in 1833 cells treated with SB431542 plus TGFβ1 we measured HGF formation and the transduction pathway involved. Altogether, HGF seemed relevant for bone-metastatic growth, being hampered by NK4 treatment, which decreased Twist more than Snail in the metastasis bulk. TGFβ1-RI blockade enhanced HGF in metastasis and adjacent bone marrow, while reducing prevalently Snail expression at the front and bulk of bone metastasis. The HGF accumulation in 1833 cells depended on an auxiliary signaling pathway, triggered by TGFβ1 under SB431542, which interfered in the transcription of HGF activator inhibitor type 1 (HAI-1) downstream of TGFβ-activated kinase 1 (TAK1): HGF stimulated Twist transactivation. In conclusion, the impairment of initial outgrowth with NK4 seemed therapeutically promising more than SB431542 chemotherapy; a functional correlation between Twist and Snail in bone metastasis seemed to be influenced by the biological stimuli of the micro-environment, and the targeting of these phenotype biomarkers might inhibit metastasis plasticity and colonization, even if it would be necessary to consider the changes of HGF levels in bone metastases undergoing TGFβ1-RI blockade.
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Gronau, Tobias, Karsten Krüger, Carina Prein, Attila Aszodi, Isabel Gronau, Renato V. Iozzo, Frank C. Mooren, et al. "Forced exercise-induced osteoarthritis is attenuated in mice lacking the small leucine-rich proteoglycan decorin." Annals of the Rheumatic Diseases 76, no. 2 (July 4, 2016): 442–49. http://dx.doi.org/10.1136/annrheumdis-2016-209319.
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ObjectiveInterterritorial regions of articular cartilage matrix are rich in decorin, a small leucine-rich proteoglycan and important structural protein, also involved in many signalling events. Decorin sequesters transforming growth factor β (TGFβ), thereby regulating its activity. Here, we analysed whether increased bioavailability of TGFβ in decorin-deficient (Dcn−/−) cartilage leads to changes in biomechanical properties and resistance to osteoarthritis (OA).MethodsUnchallenged knee cartilage was analysed by atomic force microscopy (AFM) and immunohistochemistry. Active transforming growth factor β-1 (TGFβ1) content within cultured chondrocyte supernatants was measured by ELISA. Quantitative real-time (RT)-PCR was used to analyse mRNA expression of glycosaminoglycan (GAG)-modifying enzymes in C28/I2 cells following TGFβ1 treatment. In addition, OA was induced in Dcn−/− and wild-type (WT) mice via forced exercise on a treadmill.ResultsAFM analysis revealed a strikingly higher compressive stiffness in Dcn−/− than in WT cartilage. This was accompanied by increased negative charge and enhanced sulfation of GAG chains, but not by alterations in the levels of collagens or proteoglycan core proteins. In addition, decorin-deficient chondrocytes were shown to release more active TGFβ1. Increased TGFβ signalling led to enhanced Chst11 sulfotransferase expression inducing an increased negative charge density of cartilage matrix. These negative charges might attract more water resulting in augmented compressive stiffness of the tissue. Therefore, decorin-deficient mice developed significantly less OA after forced exercise than WT mice.ConclusionsOur study demonstrates that the disruption of decorin-restricted TGFβ signalling leads to higher stiffness of articular cartilage matrix, rendering joints more resistant to OA. Therefore, the loss of an important structural component can improve cartilage homeostasis.
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Kramer, Elizabeth L., William D. Hardie, Satish K. Madala, Cynthia Davidson, and John P. Clancy. "Subacute TGFβ expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 3 (September 1, 2018): L456—L465. http://dx.doi.org/10.1152/ajplung.00530.2017.
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Cystic fibrosis (CF) produces variable lung disease phenotypes that are, in part, independent of the CF transmembrane conductance regulator ( CFTR) genotype. Transforming growth factor-β (TGFβ) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFβ is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathological TGFβ effects. A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA (Ad-TGFβ), empty vector, or PBS only. Studies were performed 1 wk after treatment, including lung mechanics, collection of bronchoalveolar lavage fluid, and analysis of lung histology, RNA, and protein. CF and non-CF mice showed similar weight loss, inflammation, goblet cell hyperplasia, and Smad pathway activation after Ad-TGFβ treatment. Ad-TGFβ produced greater abnormalities in lung mechanics in CF versus control mice, which was uniquely associated with induction of phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. CFTR transcripts were reduced, and epithelial sodium channel transcripts were increased in CF and non-CF mice, whereas the goblet cell transcription factors, forkhead ortholog A3 and SAM-pointed domain-containing ETS-like factor, were increased in non-CF but not CF mice following Ad-TGFβ treatment. Pulmonary TGFβ1 expression was sufficient to produce pulmonary remodeling and abnormalities in lung mechanics that were associated with both shared and unique cell signaling pathway activation in CF and non-CF mice. These results highlight the multifunctional impact of TGFβ on pulmonary pathology in vivo and identify cellular-response differences that may impact CF lung pathology.
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Arrighi, Nicole, Claudine Moratal, Grégoire Savary, Julien Fassy, Nicolas Nottet, Nicolas Pons, Noémie Clément, et al. "The FibromiR miR-214-3p Is Upregulated in Duchenne Muscular Dystrophy and Promotes Differentiation of Human Fibro-Adipogenic Muscle Progenitors." Cells 10, no. 7 (July 20, 2021): 1832. http://dx.doi.org/10.3390/cells10071832.
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Fibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFβ1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several “FibromiRs”, was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFβ1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFβ1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR » miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFβ axis, opening new avenues for the treatment of DMD.
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Mohammed, Javed, Andrew Gunderson, Richard Koubek, and Adam Glick. "TGFβ1 promotes adaptive immune response by modulating skin dendritic cell function and migration (147.24)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 147.24. http://dx.doi.org/10.4049/jimmunol.186.supp.147.24.
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Abstract TGFβ1 is required for the development of Langerhans cell (LC) in the skin as TGFβ1 null mice are devoid of any LC’s. While autocrine or paracrine effects of TGFβ1 have been studied in cell-specific TGFβ1 or TGFβ1RII knockout mouse models, little information is available on effects of TGFβ1 overexpression in LC function. We overexpressed active TGFβ1 in keratinocytes and monitored the paracrine effects on skin antigen presenting cell (APC) migration in vitro and in vivo. There was an increase in migration of MHC II+CD11c+ cells from ear skin following TGFβ1 overexpression by keratinocytes and a significant increase in APC migration following treatment of mouse ear skin explant with exogenous TGFβ1. Analysis of epidermal sheets following 5 days of TGFβ1 overexpression in vivo suggested an activated phenotype of APC with loss of typical dendritic morphology and increase in MHC II staining. There was enhancement in migration of skin APC’s to the skin draining lymph nodes following application of a hapten to TGFβ1 overexpressing skin. Induction of TGFβ1 in the skin 24 hrs prior to sensitization with 0.5% Dinitro-fluorobenzene resulted in increased inflammation following challenge. These results suggest that paracrine effects of TGFβ1 promote activation and migration of skin APC’s thereby enhancing skin adaptive immune response.
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Chen, Yun-Ju, Pei-Wen Hsiao, Ming-Ting Lee, J. Ian Mason, Ferng-Chun Ke, and Jiuan-Jiuan Hwang. "Interplay of PI3K and cAMP/PKA signaling, and rapamycin-hypersensitivity in TGFβ1 enhancement of FSH-stimulated steroidogenesis in rat ovarian granulosa cells." Journal of Endocrinology 192, no. 2 (February 2007): 405–19. http://dx.doi.org/10.1677/joe-06-0076.
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Transforming growth factor (TGF) β1 facilitates FSH-induced differentiation of rat ovarian granulosa cells. The signaling crosstalk between follicle stimulating hormone (FSH) and TGFβ receptors remains unclear. This study was to investigate the interplay of cAMP/protein kinase A (PKA) and phosphatidylinositol-3-kinase (PI3K) signaling including mammalian target of rapamycin (mTOR)C1 dependence in FSH- and TGFβ1-stimulated steroidogenesis in rat granulosa cells. To achieve this aim, inhibitors of PKA (PKAI), PI3K (wortmannin), and mTORC1 (rapamycin) were employed. PKAI and wortmannin suppressions of the FSH-increased progesterone production were partly attributed to decreased level of 3β-HSD, and their suppression of the FSH plus TGFβ1 effect was attributed to the reduction of all the three key players, steroidogenic acute regulatory (StAR) protein, P450scc, and 3β-HSD. Further, FSH activated the PI3K pathway including increased integrin-linked kinase (ILK) activity and phosphorylation of Akt(S473), mTOR(S2481), S6K(T389), and transcription factors particularly FoxO1(S256) and FoxO3a(S253), which were reduced by wortmannin treatment but not by PKAI. Interestingly, PKAI suppression of FSH-induced phosphorylation of cAMP regulatory element-binding protein (CREB(S133)) disappeared in the presence of wortmannin, suggesting that wortmannin may affect intracellular compartmentalization of signaling molecule(s). In addition, TGFβ1 had no effect on FSH-activated CREB and PI3K signaling mediators. We further found that rapamycin reduced the TGFβ1-enhancing effect of FSH-stimulated steroidogenesis, yet it exhibited no effect on FSH action. Surprisingly, rapamycin displayed a suppressive effect at concentrations that had no effect on mTORC1 activity. Together, this study demonstrates a delicate interplay between cAMP/PKA and PI3K signaling in FSH and TGFβ1 regulation of steroidogenesis in rat granulosa cells. Furthermore, we demonstrate for the first time that TGFβ1 acts in a rapamycin-hypersensitive and mTORC1-independent manner in augmenting FSH-stimulated steroidogenesis in rat granulosa cells.
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Almilaji, Ahmad, Jing Yan, Zohreh Hosseinzadeh, Evi Schmid, Meinrad Gawaz, and Florian Lang. "Up-Regulation of Na+/Ca2+ Exchange in Megakaryocytes Following TGFβ1 Treatment." Cellular Physiology and Biochemistry 39, no. 2 (2016): 693–99. http://dx.doi.org/10.1159/000445660.
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Background: Blood platelets are activated by increase of cytosolic Ca2+ activity ([Ca2+]i). Ca2+ entry is accomplished in part by store operated Ca2+ entry (SOCE) involving Ca2+ release activated Ca2+-channel (CRAC) moiety Orai1 and its regulator STIM1, which are stimulated by depletion of intracellular Ca2+ stores. An increase of [Ca2+]i is terminated by Na+/Ca2+-exchange. The expression of both, Orai1 and STIM1 in megakaryocytes is up-regulated by tumor growth factor TGFβ1, a powerful regulator of megakaryocyte differentiation. The present study explored whether TGFβ1 similarly modifies megakaryocyte Na+/Ca2+-exchanger activity. Methods: [Ca2+]i was determined utlizing Fura-2 fluorescence, SOCE from increase of [Ca2+]i, following readdition of extracellular Ca2+ after store depletion, and Na+/Ca2+-exchanger activity from increase of [Ca2+]i and whole cell currents following removal of extracellular Na+. Results: TGFβ1 treatment not only augments the increase of [Ca2+]i following store depletion and SOCE, but significantly up-regulates Na+/Ca2+-exchanger activity as apparent from [Ca2+]i measurements and whole cell currents. Conclusions: TGFβ1 is a powerful stimulator of both, SOCE and Na+/Ca2+-exchanger activity in megakaryocytes.
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Samon, Jeremy B., Ameya Champhekar, Lisa M. Minter, Janice C. Telfer, Lucio Miele, Abdul Fauq, Pritam Das, Todd E. Golde, and Barbara A. Osborne. "Notch1 and TGFβ1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells." Blood 112, no. 5 (September 1, 2008): 1813–21. http://dx.doi.org/10.1182/blood-2008-03-144980.
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Abstract Notch and its ligands have been implicated in the regulation and differentiation of various CD4+ T-helper cells. Regulatory T cells (Tregs), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that transforming growth factor beta (TGFβ1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using γ-secretase inhibitor (GSI) treatment blocks (1) TGFβ1-induced Foxp3 expression, (2) the up-regulation of Foxp3-target genes, and (3) the ability to suppress naive T-cell proliferation. In addition, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and development of symptoms consistent with autoimmune hepatitis, a disease previously found to result from dysregulation of TGFβ signaling and regulatory T cells. Together, these findings indicate that the Notch and TGFβ signaling pathways cooperatively regulate Foxp3 expression and regulatory T-cell maintenance both in vitro and in vivo.
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Farina, G., R. Lemaire, P. Pancari, J. Bayle, R. L. Widom, and R. Lafyatis. "Cartilage oligomeric matrix protein expression in systemic sclerosis reveals heterogeneity of dermal fibroblast responses to transforming growth factor β." Annals of the Rheumatic Diseases 68, no. 3 (April 13, 2008): 435–41. http://dx.doi.org/10.1136/ard.2007.086850.
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Objective:Cartilage oligomeric matrix protein (COMP) accumulates in systemic sclerosis (SSc) skin and is upregulated by transforming growth factor (TGF)β. To further characterise the response to TGFβ in SSc, we investigated TGFβ1 and COMP expression and myofibroblast staining in SSc skin.Methods:Skin biopsies from patients with diffuse cutaneous SSc (dSSc), limited cutaneous SSc (lSSc) and healthy controls were evaluated for COMP mRNA expression using real-time PCR. COMP, α-smooth muscle actin (SMA) and TGFβ were assessed in skin sections and in cultured fibroblasts by immunohistochemistry. Clinical disease status was assessed by the modified Rodnan skin score (mRSS).Results:Myofibroblasts expressing SMA and COMP were found coexpressed in many cells in dSSc dermis, but each also stained distinct cells in the dermis. Cultured SSc dermal fibroblasts also showed heterogeneity for COMP and SMA expression, with cells expressing SMA, COMP, both or neither. TGFβ treatment increased COMP and SMA-expressing cells. COMP mRNA expression in lesional skin from patients with dSSc correlated with the mRSS and TGFβ1 staining.Conclusion:These findings suggest that TGFβ upregulation of COMP and/or SMA expression in subpopulations of fibroblasts contributes to different pathways of fibrosis and that multiple TGFβ regulated genes may serve as biomarkers for the degree of SSc skin involvement.
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Ünlü, A., and R. E. Leake. "Transforming Growth Factor β1 Stimulates Urokinase Plasminogen Activator System on Prostate Cancer Cells." International Journal of Biological Markers 18, no. 2 (April 2003): 147–51. http://dx.doi.org/10.1177/172460080301800208.
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The effect of TGFβ1 on the proliferation and plasminogen activator system (PA) of two prostate carcinoma cell lines, PC3 and DU145, was investigated. PA, particularly urokinase plasminogen activator (uPA), has been implicated in extracellular proteolysis, local invasiveness, metastatic spread and angiogenesis. High levels of uPA and plasminogen activator inhibitor-1 (PAI-1) correlate with poor prognosis in several cancers. TGFβ1 had no significant effect on the proliferation of either cell line. TGFβ1 increased the production of uPA in PC3 and DU145 cells. Despite the very low PAI-1 protein levels in both cell lines, TGFβ1 treatment resulted in a remarkable increase in PAI-1 secretion. PAI-2 protein was also increased by 59% in the PC3 cells. A divergent effect of TGFβ1 on the uPA enzyme activity was observed (28% decrease in PC3 and 131% increase in DU145 cells). Overall, TGFβ1 treatment did not affect the invasion of reconstituted basement membrane of PC3 cells. In addition to the uPA:PAI-1 ratio, the presence of PAI-2 may be an important factor in the determination of metastatic sites for prostate cancer cells. In conclusion, the potential contribution of TGFβ1 to tumor invasion may be considered as positive, based on both loss of growth inhibition and stimulation of components of the invasive system of prostate carcinoma.
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Joshi, Pratibha, Aida Venado, Tiana Curry-McCoy, and David Guidot. "Activation of membrane TGFβ1 on alveolar macrophages by co-cultured alcohol primed alveolar epithelial cells (111.1)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 111.1. http://dx.doi.org/10.4049/jimmunol.186.supp.111.1.
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Abstract Alcohol abuse impairs pulmonary innate immunity rendering individuals susceptible to pneumonia. We have previously shown that alcohol abuse causes oxidative stress in the lung and increases TGFβ1 expression. TGFβ1 downregulates GM-CSF receptors resulting in the alveolar macrophage and epithelial cell dysfunction. However, the exact mechanism of alcohol-mediated activation of TGFβ1 in vivo is still under investigation. We examined TGFβ1 expression on alveolar macrophages and epithelial cells from control- and alcohol-fed rats by real time PCR and flow cytometry. TGFβ1 gene expression was significantly higher in alcoholic macrophages and TGFβ1 protein was predominantly membrane bound in macrophages. In addition, as compared to control, alveolar epithelial cells from alcohol-fed rats had significantly higher expression of alpha5 integrin chain that is implicated in TGFβ1 activation. Therefore, we hypothesized that alcohol-induced increase in epithelial alpha5 would activate membrane TGFβ1 on macrophages. To examine this, macrophage (NR8383) and epithelial (L2) cell lines were co-cultured on transwell membranes to assess the changes in paracellular permeability. Only alcohol primed co-cultures showed a decrease in epithelial barrier function that was reversed by anti-TGFβ1 treatment. Taken together, these results suggest that cellular contact between alveolar macrophages and epithelial cells is essential for alcohol mediated activation of TGFβ1 in the lung.
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Fernando, Josephine, and John Ryan. "TGF-β1 suppresses mast cell functions in vivo. (151.15)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 151.15. http://dx.doi.org/10.4049/jimmunol.186.supp.151.15.
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Abstract We have previously demonstrated the immunosuppressive effects of TGFβ1 on IgE signaling in human and mouse mast cells in vitro. Here we extend our focus to in vivo models, including mast cell-dependent airway inflammation. TGFβ1 injection into unimmunized mice reduced peritoneal mast cell numbers and their expression of the high affinity IgE receptor, as well as cKit. Further, TGFβ1 delivered as an aerosol to ovalbumin-immunized mice decreased pulmonary eosinophilic inflammation and mucus production. TGFβ1 did not affect Syk, Stat5, Fyn or Akt mRNA expression. However, mast cell Fyn and Stat5 protein levels were diminished by TGFβ1 treatment in vitro, while Akt and Syk were unaffected. Interestingly, we found that mast cells from the 129/SvJ mouse strain were resistant to TGFβ1-mediated suppression. Unlike their C57BL/6 counterparts, 129/SvJ mast cells did not demonstrate reduced IgE receptor expression or IgE-mediated cytokine production after culture with TGFβ1. These data show that TGFβ1 is a potent suppressor of the mast cell response that may be altered by host genetic makeup. We further find that the effects of TGFβ1 include selective reduction in key IgE-mediated signaling molecules.
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Sharkey, D. J., R. B. Gilchrist, and S. A. Robertson. "176. GDF-9, BMP-15 AND ACTIVIN A CONTRIBUTE TO SEMINAL FLUID SIGNALLING IN HUMAN CERVICAL EPITHELIAL CELLS." Reproduction, Fertility and Development 21, no. 9 (2009): 94. http://dx.doi.org/10.1071/srb09abs176.
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We have previously shown that in women, as in animal species, introduction of seminal fluid at coitus induces cytokine expression and a local inflammatory-like response in the female reproductive tract. The response is characterised by induction of mRNAs encoding several pro-inflammatory cytokines including GM-CSF, IL-1α and IL-6, as well as chemokines IL-8, MIP-3α and MCP-1. Recent studies in our laboratory have focused on identifying active signalling agents present in human seminal plasma. To date we have shown that all three mammalian isoforms of TGFβ (TGFβ1, TGFβ2 and TGFβ3) and 19-hydroxy PGE are key regulators of this response. The current study aimed to determine whether other members of the TGFβ superfamily including GDF-9, BMP-15 and Activin A also contribute. To investigate this we utilised immortalised Ect1 ectocervical epithelial cells, which mimic the response of primary ectocervical epithelial cells. Ect1 cells were incubated with increasing doses (0.5, 5.0, 50 or 500 ng/ml) of rGDF-9, rBMP-15 or rActivin A and production of pro-inflammatory cytokines and chemokines was assessed in 24 hour post-treatment supernatants using Luminex microbead technology. BMP-15 was found to stimulate GM-CSF production (2-fold), while GDF-9 and Activin A both stimulated IL-6 production (2.4-fold and 80% increases respectively), all acting in a dose-dependent manner. In contrast, all three factors inhibited IL-8 production by Ect1 cells. These data demonstrate that GDF-9, BMP-15 and Activin A are new seminal fluid signalling agents capable of targeting female reproductive tract epithelial cells and inducing different response profiles compared with TGFβ and 19-hydroxy PGE. The relative bioavailability of these factors in seminal fluid would therefore influence the profile of inflammatory response in the female partner, regulating immune responses to male seminal antigens as well as sexually transmitted pathogens.
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Sharma, Shweta, Rishov Goswami, Michael Merth, Jonathan Cohen, Kai Y. Lei, David X. Zhang, and Shaik O. Rahaman. "TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation." American Journal of Physiology-Cell Physiology 312, no. 5 (May 1, 2017): C562—C572. http://dx.doi.org/10.1152/ajpcell.00187.2016.
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Scleroderma is a multisystem fibroproliferative disease with no effective medical treatment. Myofibroblasts are critical to the fibrogenic tissue repair process in the skin and many internal organs. Emerging data support a role for both matrix stiffness, and transforming growth factor β1 (TGFβ1), in myofibroblast differentiation. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel activated by both mechanical and biochemical stimuli. The objective of this study was to determine the role of TRPV4 in TGFβ1- and matrix stiffness-induced differentiation of dermal fibroblasts. We found that TRPV4 channels are expressed and functional in both human (HDF) and mouse (MDF) dermal fibroblasts. TRPV4 activity (agonist-induced Ca2+ influx) was induced by both matrix stiffness and TGFβ1 in dermal fibroblasts. TGFβ1 induced expression of TRPV4 proteins in a dose-dependent manner. Genetic ablation or pharmacological antagonism of TRPV4 channel abrogated Ca2+ influx and both TGFβ1-induced and matrix stiffness-induced myofibroblast differentiation as assessed by 1) α-smooth muscle actin expression/incorporation into stress fibers, 2) generation of polymerized actin, and 3) expression of collagen-1. We found that TRPV4 inhibition abrogated TGFβ1-induced activation of AKT but not of Smad2/3, suggesting that the mechanism by which profibrotic TGFβ1 signaling in dermal fibroblasts is modified by TRPV4 may be through non-Smad pathways. Altogether, these data identify a novel reciprocal functional link between TRPV4 activation and TGFβ1 signals regulating dermal myofibroblast differentiation. These findings suggest that therapeutic inhibition of TRPV4 activity may provide a targeted approach to the treatment of scleroderma.
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Welsh, Brian T., Ryan Faucette, Sanela Bilic, Constance J. Martin, Thomas Schürpf, David Chen, Samantha Nicholls, Janice Lansita, and Ashish Kalra. "Nonclinical Development of SRK-181: An Anti-Latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors." International Journal of Toxicology 40, no. 3 (March 19, 2021): 226–41. http://dx.doi.org/10.1177/1091581821998945.
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Checkpoint inhibitors offer a promising immunotherapy strategy for cancer treatment; however, due to primary or acquired resistance, many patients do not achieve lasting clinical responses. Recently, the transforming growth factor-β (TGFβ) signaling pathway has been identified as a potential target to overcome primary resistance, although the nonselective inhibition of multiple TGFβ isoforms has led to dose-limiting cardiotoxicities. SRK-181 is a high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. To support SRK-181 clinical development, we present here a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies showed that SRK-181 has no effect on human platelet function and does not induce cytokine release in human peripheral blood. Four-week toxicology studies with SRK-181 showed that weekly intravenous administration achieved sustained serum exposure and was well tolerated in rats and monkeys, with no treatment-related adverse findings. The no-observed-adverse-effect levels levels were 200 mg/kg in rats and 300 mg/kg in monkeys, the highest doses tested, and provide a nonclinical safety factor of up to 813-fold (based on Cmax) above the phase 1 starting dose of 80 mg every 3 weeks. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that SRK-181 is a selective inhibitor of latent TGFβ1 that does not produce the nonclinical toxicities associated with nonselective TGFβ inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.
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Collins, A. T., E. J. Robinson, and D. E. Neal. "Benign prostatic stromal cells are regulated by basic fibroblast growth factor and transforming growth factor-β1." Journal of Endocrinology 151, no. 2 (November 1996): 315–22. http://dx.doi.org/10.1677/joe.0.1510315.
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Abstract The current study was undertaken, using cultures of prostatic epithelial and stromal cells, to determine the functional interactions between androgens, basic fibroblast growth factor (FGF2) and transforming growth factor-β1 (TGFβ1) and their importance in maintaining stromal homeostasis. Treatment of stromal cells with TGFβ1 significantly increased intracellular FGF2 and FGF2 sequestered to the extracellular matrix. FGF2 was also detected in stromal conditioned medium (SCM), but at levels 70-fold less than found in cell lysates. TGFβ1 (0·1 ng/ml) treatment caused an initial increase of 86% in secreted FGF2 levels, but high concentrations of TGFβ1 (5 ng/ml) decreased FGF2 levels by 38%, relative to the untreated control. Further studies showed that epithelial conditioned medium (ECM), androgen-treated, stromal conditioned medium (ASCM), but not SCM were mitogenic for stromal cells. Both ECM and ASCM caused a threefold increase in DNA synthesis. FGF2 may be the mediator of these interactions, since the mitogenic effect of both ECM and ASCM was significantly reduced by the addition of anti-FGF2 neutralising antibody. We hypothesise that the lack of response of stromal cells to SCM is due to TGFβ1 blocking the mitogenic effect of FGF2. Thus down-regulation of TGFβ1 synthesis, by androgens, results in stromal proliferation by ASCM. Journal of Endocrinology (1996) 151, 315–322