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1
Elderbroom, Jennifer L., Jennifer J. Huang, Catherine E. Gatza, Jian Chen, Tam How, Mark Starr, Andrew B. Nixon, and Gerard C. Blobe. "Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion." Molecular Biology of the Cell 25, no. 16 (August 15, 2014): 2320–32. http://dx.doi.org/10.1091/mbc.e13-09-0524.
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The type III transforming growth factor β (TGF-β) receptor (TβRIII), also known as betaglycan, is the most abundantly expressed TGF-β receptor. TβRIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. TβRIII binds TGF-β ligands, with membrane-bound TβRIII presenting ligand to enhance TGF-β signaling. However, TβRIII can also undergo ectodomain shedding, releasing soluble TβRIII, which binds and sequesters ligand to inhibit downstream signaling. To investigate the relative contributions of soluble and membrane-bound TβRIII on TGF-β signaling and breast cancer biology, we defined TβRIII mutants with impaired (ΔShed-TβRIII) or enhanced ectodomain shedding (SS-TβRIII). Inhibiting ectodomain shedding of TβRIII increased TGF-β responsiveness and abrogated TβRIII's ability to inhibit breast cancer cell migration and invasion. Conversely, expressing SS-TβRIII, which increased soluble TβRIII production, decreased TGF-β signaling and increased TβRIII-mediated inhibition of breast cancer cell migration and invasion. Of importance, SS-TβRIII–mediated increases in soluble TβRIII production also reduced breast cancer metastasis in vivo. Taken together, these studies suggest that the ratio of soluble TβRIII to membrane-bound TβRIII is an important determinant for regulation of TβRIII- and TGF-β–mediated signaling and biology.
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Kim, Pyeung-Hyeun, Young-Saeng Jang, Ha-Eon Song, Goo-Young Seo, Seung-Goo Kang, Jeong Hyun Lee, Bo-Eun Kwon, and Hyun-Jeong Ko. "Mechanism underlying the induction of Foxp3+ regulatory T cells by lactoferrin." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 47.16. http://dx.doi.org/10.4049/jimmunol.200.supp.47.16.
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Abstract Lactoferrin (LF) is multifunctional in the immune response. We have previously demonstrated that LF acts like TGF-β in IgA B cell differentiation. Therein, we explored whether LF affects peripheral regulatory T cell (Treg) differentiation. Indeed, LF induced Foxp3+ Treg differentiation by itself and in combination with TGF-β1 synergized to express Foxp3. It was conceivable that LF may increase Foxp3 expression through secretion of active TGF-β or facilitating latent TGF-β to active form. There was little active TGF-β in the supernatant from LF-stimulated T cells. Surprisingly, however, pan anti-TGFβ Ab completely abolished the LF-induced Foxp3 expression, suggesting that membrane-bound TGF-β may be involved. In this, we found that both LF and TGF-β1 increase latency-associated peptide negative (LAP−)TGF-β on the surface of Foxp3+T cells, and this increase was more dramatic when treated with LF plus TGF-β1. As was the case in B cells, LF-induced Foxp3 expression was virtually disappeared by pretreatment with soluble TβRIII. Collectively, these results suggest that LF induces Foxp3+Treg through TβRIII and subsequent expression of membrane-bound/LAP-negative TGF-β.
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Yan, Xiaohua, and Ye-Guang Chen. "Smad7: not only a regulator, but also a cross-talk mediator of TGF-β signalling." Biochemical Journal 434, no. 1 (January 27, 2011): 1–10. http://dx.doi.org/10.1042/bj20101827.
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TGF-β (transforming growth factor-β) is a pleiotropic cytokine regulating diverse cellular processes. It signals through membrane-bound receptors, downstream Smad proteins and/or other signalling mediators. Smad7 has been well established to be a key negative regulator of TGF-β signalling. It antagonizes TGF-β signalling through multiple mechanisms in the cytoplasm and in the nucleus. Smad7 can be transcriptionally induced by TGF-β and other growth factors and serves as an important cross-talk mediator of the TGF-β signalling pathway with other signalling pathways. Accordingly, it plays pivotal roles in embryonic development and adult homoeostasis, and altered expression of Smad7 is often associated with human diseases, such as cancer, tissue fibrosis and inflammatory diseases.
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Kim, Sun Kyung, Morkos A. Henen, and Andrew P. Hinck. "Structural biology of betaglycan and endoglin, membrane-bound co-receptors of the TGF-beta family." Experimental Biology and Medicine 244, no. 17 (October 10, 2019): 1547–58. http://dx.doi.org/10.1177/1535370219881160.
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Betaglycan and endoglin, membrane-bound co-receptors of the TGF-β family, are required to mediate the signaling of a select subset of TGF-β family ligands, TGF-β2 and InhA, and BMP-9 and BMP-10, respectively. Previous biochemical and biophysical methods suggested alternative modes of ligand binding might be responsible for these co-receptors to selectively recognize and potentiate the functions of their ligands, yet the molecular details were lacking. Recent progress determining structures of betaglycan and endoglin, both alone and as bound to their cognate ligands, is presented herein. The structures reveal relatively minor, but very significant structural differences that lead to entirely different modes of ligand binding. The different modes of binding nonetheless share certain commonalities, such as multivalency, which imparts the co-receptors with very high affinity for their cognate ligands, but at the same time provides a mechanism for release by stepwise binding of the signaling receptors, both of which are essential for their functions. Impact statement The TGF-β family is one of the most highly diversified signaling families, with essential roles in nearly all aspects of metazoan biology. Though functionally diverse, all 33 human TGF-β family ligands signal through a much more limited number of receptors. Thus the signaling repertoire is limited and cannot account for the functional diversity of signaling ligands in vivo. This mini review covers recent advances in our understanding of the structural basis by which two co-receptors of the family, betaglycan and endoglin, selectively recognize a limited subset of TGF-β family ligands and enable their functions in the cells and tissues in which they are expressed. The advances described also highlight gaps in current understanding of how the co-receptors are displaced upon engagement by the signaling receptors and how they function in a physiological environment, and thus suggest new avenues for investigation that will further illuminate how these essential co-receptors function in vivo.
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Sisto, Margherita, Domenico Ribatti, and Sabrina Lisi. "SMADS-Mediate Molecular Mechanisms in Sjögren’s Syndrome." International Journal of Molecular Sciences 22, no. 6 (March 21, 2021): 3203. http://dx.doi.org/10.3390/ijms22063203.
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There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren’s syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic target for pSS.
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Weber, Florian, Oliver Treeck, Patricia Mester, and Christa Buechler. "Expression and Function of BMP and Activin Membrane-Bound Inhibitor (BAMBI) in Chronic Liver Diseases and Hepatocellular Carcinoma." International Journal of Molecular Sciences 24, no. 4 (February 9, 2023): 3473. http://dx.doi.org/10.3390/ijms24043473.
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BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) is a transmembrane pseudoreceptor structurally related to transforming growth factor (TGF)-β type 1 receptors (TGF-β1Rs). BAMBI lacks a kinase domain and functions as a TGF-β1R antagonist. Essential processes such as cell differentiation and proliferation are regulated by TGF-β1R signaling. TGF-β is the best-studied ligand of TGF-βRs and has an eminent role in inflammation and fibrogenesis. Liver fibrosis is the end stage of almost all chronic liver diseases, such as non-alcoholic fatty liver disease, and at the moment, there is no effective anti-fibrotic therapy available. Hepatic BAMBI is downregulated in rodent models of liver injury and in the fibrotic liver of patients, suggesting that low BAMBI has a role in liver fibrosis. Experimental evidence convincingly demonstrated that BAMBI overexpression is able to protect against liver fibrosis. Chronic liver diseases have a high risk of hepatocellular carcinoma (HCC), and BAMBI was shown to exert tumor-promoting as well as tumor-protective functions. This review article aims to summarize relevant studies on hepatic BAMBI expression and its role in chronic liver diseases and HCC.
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Gallardo-Vara, Ruiz-Llorente, Casado-Vela, Ruiz-Rodríguez, López-Andrés, Pattnaik, Quintanilla, and Bernabeu. "Endoglin Protein Interactome Profiling Identifies TRIM21 and Galectin-3 as New Binding Partners." Cells 8, no. 9 (September 13, 2019): 1082. http://dx.doi.org/10.3390/cells8091082.
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Endoglin is a 180-kDa glycoprotein receptor primarily expressed by the vascular endothelium and involved in cardiovascular disease and cancer. Heterozygous mutations in the endoglin gene (ENG) cause hereditary hemorrhagic telangiectasia type 1, a vascular disease that presents with nasal and gastrointestinal bleeding, skin and mucosa telangiectases, and arteriovenous malformations in internal organs. A circulating form of endoglin (alias soluble endoglin, sEng), proteolytically released from the membrane-bound protein, has been observed in several inflammation-related pathological conditions and appears to contribute to endothelial dysfunction and cancer development through unknown mechanisms. Membrane-bound endoglin is an auxiliary component of the TGF-β receptor complex and the extracellular region of endoglin has been shown to interact with types I and II TGF-β receptors, as well as with BMP9 and BMP10 ligands, both members of the TGF-β family. To search for novel protein interactors, we screened a microarray containing over 9000 unique human proteins using recombinant sEng as bait. We find that sEng binds with high affinity, at least, to 22 new proteins. Among these, we validated the interaction of endoglin with galectin-3, a secreted member of the lectin family with capacity to bind membrane glycoproteins, and with tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin-protein ligase. Using human endothelial cells and Chinese hamster ovary cells, we showed that endoglin co-immunoprecipitates and co-localizes with galectin-3 or TRIM21. These results open new research avenues on endoglin function and regulation.
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Dhandapani, Krishnan M., F. Marlene Wade, Virendra B. Mahesh, and Darrell W. Brann. "Astrocyte-Derived Transforming Growth Factor-β Mediates the Neuroprotective Effects of 17β-Estradiol: Involvement of Nonclassical Genomic Signaling Pathways." Endocrinology 146, no. 6 (June 1, 2005): 2749–59. http://dx.doi.org/10.1210/en.2005-0014.
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Abstract 17β-Estradiol (E2) and selective estrogen receptor modulators (SERMs), such as tamoxifen, mediate numerous effects in the brain, including neurosecretion, neuroprotection, and the induction of synaptic plasticity. Astrocytes, the most abundant cell type in the brain, influence many of these same functions and thus may represent a mediator of estrogen action. The present study examined the regulatory effect and underlying cell signaling mechanisms of E2-induced release of neurotropic growth factors from primary rat cortical astrocyte cultures. The results revealed that E2 (0.5, 1, and 10 nm) and tamoxifen (1 μm) increased both the expression and release of the neuroprotective cytokines, TGF-β1 and TGF-β2 (TGF-β), from cortical astrocytes. The stimulatory effect of E2 was attenuated by the estrogen receptor (ER) antagonist, ICI182,780, suggesting ER dependency. The effect of E2 also appeared to involve mediation by the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway, because E2 rapidly induced Akt phosphorylation, and pharmacological or molecular inhibition of the PI3K/Akt pathway prevented E2-induced release of TGF-β. Additionally, the membrane-impermeant conjugate, E2-BSA, stimulated the release of TGF-β, suggesting the potential involvement of a membrane-bound ER. Finally, E2, tamoxifen, and E2-BSA were shown to protect neuronal-astrocyte cocultures from camptothecin-induced neuronal cell death, effects that were attenuated by ICI182,780, Akt inhibition, or TGF-β immunoneutralization. As a whole, these studies suggest that E2 induction of TGF-β release from cortical astrocytes could provide a mechanism of neuroprotection, and that E2 stimulation of TGF-β expression and release from astrocytes occurs via an ER-dependent mechanism involving mediation by the PI3K/Akt signaling pathway.
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Jang, Young-Saeng, Ha-Eon Song, Goo-Young Seo, Hyeon-Ju Jo, Sunhee Park, Hui-Won Park, Tae-Gyu Kim, et al. "Lactoferrin Potentiates Inducible Regulatory T Cell Differentiation through TGF-β Receptor III Binding and Activation of Membrane-Bound TGF-β." Journal of Immunology 207, no. 10 (October 6, 2021): 2456–64. http://dx.doi.org/10.4049/jimmunol.2100326.
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Zhu, Qingwei, Yong Hwan Kim, Douglas Wang, S. Paul Oh, and Kunxin Luo. "SnoN facilitates ALK1–Smad1/5 signaling during embryonic angiogenesis." Journal of Cell Biology 202, no. 6 (September 9, 2013): 937–50. http://dx.doi.org/10.1083/jcb.201208113.
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In endothelial cells, two type I receptors of the transforming growth factor β (TGF-β) family, ALK1 and ALK5, coordinate to regulate embryonic angiogenesis in response to BMP9/10 and TGF-β. Whereas TGF-β binds to and activates ALK5, leading to Smad2/3 phosphorylation and inhibition of endothelial cell proliferation and migration, BMP9/10 and TGF-β also bind to ALK1, resulting in the activation of Smad1/5. SnoN is a negative regulator of ALK5 signaling through the binding and repression of Smad2/3. Here we uncover a positive role of SnoN in enhancing Smad1/5 activation in endothelial cells to promote angiogenesis. Upon ligand binding, SnoN directly bound to ALK1 on the plasma membrane and facilitated the interaction between ALK1 and Smad1/5, enhancing Smad1/5 phosphorylation. Disruption of this SnoN–Smad interaction impaired Smad1/5 activation and up-regulated Smad2/3 activity. This resulted in defective angiogenesis and arteriovenous malformations, leading to embryonic lethality at E12.5. Thus, SnoN is essential for TGF-β/BMP9-dependent biological processes by its ability to both positively and negatively modulate the activities of Smad-dependent pathways.
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Yang, Young, and Sujeong Park. "Abstract LB010: LY6K depletion modulates TGF-β and EGF signaling." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB010. http://dx.doi.org/10.1158/1538-7445.am2023-lb010.
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Abstract Lymphocyte antigen 6 complex locus K (LY6K), a glycosylphosphatidylinositol-anchored protein, plays a dynamic role in cancer metastasis. In the current study, we deciphered the effects of LY6K on transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) signaling through clathrin- and caveolin-1 (CAV-1)-mediated endocytosis. LY6K expression level is elevated in higher grade cervical cancer patients correlating with poor overall survival, progression-free survival, and disease-free survival. LY6K-depletion in HeLa and SiHa cancer cells suppressed EGF-induced proliferation and TGF-β-enhanced migration and invasion. Both TGF-β receptor-I (TβRI) and EGF receptor (EGFR) localized at the plasma membrane regardless of LY6K expression, and LY6K bound TβRI irrespective of the presence of TGF-β; however, LY6K did not bind EGFR. LY6K-depleted cells showed impaired SMAD2 phosphorylation upon TGF-β treatment and lower proliferation rates following long-term treatment with EGF. We revealed the atypical movement of TβRI and EGFR from plasma membrane upon ligand stimulation in LY6K-depleted cells and an impaired movement of the endocytic proteins clathrin and CAV-1. Subsequently, transmission electron microscopy showed no clathrin and CAV-1-coated vesicles in LY6K-depleted cells. Our study demonstrates the key role of LY6K in both clathrin- and CAV-1-mediated endocytic pathways regulated by TGF-β and EGF, and it suggests a correlation between LY6K overexpression in cervical cancer cells and poor overall survival. Citation Format: Young Yang, Sujeong Park. LY6K depletion modulates TGF-β and EGF signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB010.
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Juárez, Patricia, M. Magdalena Vilchis-Landeros, José Ponce-Coria, Valentín Mendoza, Rogelio Hernández-Pando, Norma A. Bobadilla, and Fernando López-Casillas. "Soluble betaglycan reduces renal damage progression in db/db mice." American Journal of Physiology-Renal Physiology 292, no. 1 (January 2007): F321—F329. http://dx.doi.org/10.1152/ajprenal.00264.2006.
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Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of renal diseases. Betaglycan, also known as the type III TGF-β receptor, regulates TGF-β action by modulating its access to the type I and II receptors. Betaglycan potentiates TGF-β; however, soluble betaglycan, which is produced by the shedding of the membrane-bound receptor, is a potent antagonist of TGF-β. In the present work, we have used a recombinant form of soluble betaglycan (SBG) to prevent renal damage in genetically obese and diabetic db/db mice. Eight-wk-old db/db or nondiabetic ( db/m) mice were injected intraperitoneally with 50 μg of SBG or vehicle alone three times a wk for 8 wk. The db/db mice that received vehicle presented albuminuria and increased serum creatinine, as well as glomerular mesangial matrix expansion. The db/db mice treated with SBG exhibited a reduction in serum creatinine, albuminuria, and structural renal damage. These effects were associated with lower kidney levels of mRNAs encoding TGF-β1, TGF-β2, TGF-β3, collagen IV, collagen I, fibronectin, and serum glucocorticoid kinase as well as a reduction in the immunostaining of collagen IV and fibronectin. Our data indicate that SBG is a renoprotective agent that neutralized TGF-β actions in this model of nephropathy. Because SBG has a high affinity for all TGF-β isoforms, in particular TGF-β2, it is found naturally in serum and tissues and its shedding may be regulated. We believe that SBG shall prove convenient for long-term treatment of kidney diseases and other pathologies in which TGF-β plays a pathophysiological role.
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Jonuleit, Helmut, Edgar Schmitt, Hacer Kakirman, Michael Stassen, Jürgen Knop, and Alexander H. Enk. "Infectious Tolerance." Journal of Experimental Medicine 196, no. 2 (July 15, 2002): 255–60. http://dx.doi.org/10.1084/jem.20020394.
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Regulatory CD4+CD25+ T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact–mediated suppression of conventional CD4+ T cells by human CD25+ Treg cells is fixation resistant, independent from membrane-bound TGF-β but requires activation and protein synthesis of CD25+ Treg cells. Coactivation of CD25+ Treg cells with Treg cell–depleted CD4+ T cells results in anergized CD4+ T cells that in turn inhibit the activation of conventional, freshly isolated CD4+ T helper (Th) cells. This infectious suppressive activity, transferred from CD25+ Treg cells via cell contact, is cell contact–independent and partially mediated by soluble transforming growth factor (TGF)-β. The induction of suppressive properties in conventional CD4+ Th cells represents a mechanism underlying the phenomenon of infectious tolerance. This explains previously published conflicting data on the role of TGF-β in CD25+ Treg cell–induced immunosuppression.
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Koinuma, Daizo, Shuichi Tsutsumi, Naoko Kamimura, Hirokazu Taniguchi, Keiji Miyazawa, Makoto Sunamura, Takeshi Imamura, Kohei Miyazono, and Hiroyuki Aburatani. "Chromatin Immunoprecipitation on Microarray Analysis of Smad2/3 Binding Sites Reveals Roles of ETS1 and TFAP2A in Transforming Growth Factor β Signaling." Molecular and Cellular Biology 29, no. 1 (October 27, 2008): 172–86. http://dx.doi.org/10.1128/mcb.01038-08.
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ABSTRACT The Smad2 and Smad3 (Smad2/3) proteins are principally involved in the transmission of transforming growth factor β (TGF-β) signaling from the plasma membrane to the nucleus. Many transcription factors have been shown to cooperate with the Smad2/3 proteins in regulating the transcription of target genes, enabling appropriate gene expression by cells. Here we identified 1,787 Smad2/3 binding sites in the promoter regions of over 25,500 genes by chromatin immunoprecipitation on microarray in HaCaT keratinocytes. Binding elements for the v-ets erythroblastosis virus E26 oncogene homolog (ETS) and transcription factor AP-2 (TFAP2) were significantly enriched in Smad2/3 binding sites, and knockdown of either ETS1 or TFAP2A resulted in overall alteration of TGF-β-induced transcription, suggesting general roles for ETS1 and TFAP2A in the transcription induced by TGF-β-Smad pathways. We identified novel Smad binding sites in the CDKN1A gene where Smad2/3 binding was regulated by ETS1 and TFAP2A. Moreover, we showed that small interfering RNAs for ETS1 and TFAP2A affected TGF-β-induced cytostasis. We also analyzed Smad2- or Smad3-specific target genes regulated by TGF-β and found that their specificity did not appear to be solely determined by the amounts of the Smad2/3 proteins bound to the promoters. These findings reveal novel regulatory mechanisms of Smad2/3-induced transcription and provide an essential resource for understanding their roles.
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Kudipudi, Pradeep K., Sebastian P. Galuska, Raimund Dietze, Georgios Scheiner-Bobis, Kate L. Loveland, and Lutz Konrad. "Betaglycan (TβRIII) is a Key Factor in TGF-β2 Signaling in Prepubertal Rat Sertoli Cells." International Journal of Molecular Sciences 20, no. 24 (December 9, 2019): 6214. http://dx.doi.org/10.3390/ijms20246214.
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Transforming growth factor-βs (TGF-βs) signal after binding to the TGF-β receptors TβRI and TβRII. Recently, however, betaglycan (BG) was identified as an important co-receptor, especially for TGF-β2. Both proteins are involved in several testicular functions. Thus, we analyzed the importance of BG for TGF-β1/2 signaling in Sertoli cells with ELISAs, qRT-PCR, siRNA silencing and BrdU assays. TGF-β1 as well as TGF-β2 reduced shedding of membrane-bound BG (mBG), thus reducing the amount of soluble BG (sBG), which is often an antagonist to TGF-β signaling. Treatment of Sertoli cells with GM6001, a matrix metalloproteinases (MMP) inhibitor, also counteracted BG shedding, thus suggesting MMPs to be mainly involved in shedding. Interestingly, TGF-β2 but not TGF-β1 enhanced secretion of tissue inhibitor of metalloproteinases 3 (TIMP3), a potent inhibitor of MMPs. Furthermore, recombinant TIMP3 attenuated BG shedding. Co-stimulation with TIMP3 and TGF-β1 reduced phosphorylation of Smad3, while a combination of TIMP3/TGF-β2 increased it. Silencing of BG as well as TIMP3 reduced TGF-β2-induced phosphorylation of Smad2 and Smad3 significantly, once more highlighting the importance of BG for TGF-β2 signaling. In contrast, this effect was not observed with TIMP3/TGF-β1. Silencing of BG and TIMP3 decreased significantly Sertoli cell proliferation. Taken together, BG shedding serves a major role in TGF-β2 signaling in Sertoli cells.
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Vega, Jose L., Daniel Saban, Yejun Carrier, Sharmila Masli, and Howard L. Weiner. "Retinal Pigment Epithelial Cells Induce foxp3+Regulatory T Cells via Membrane-bound TGF-β." Ocular Immunology and Inflammation 18, no. 6 (October 2010): 459–69. http://dx.doi.org/10.3109/09273948.2010.509532.
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Bardhan, Kankana, Nikolaos Patsoukis, Alexandra Plessa, Niko Tsopoulidis, Duygu Sari, Lequn Li, and Vassiliki A. Boussiotis. "Rap1-GTP Augments TGF-b-Mediated Signaling in T Lymphocytes Via a Mechanism Dependent on the b Chain of LFA-1 Integrin." Blood 126, no. 23 (December 3, 2015): 3422. http://dx.doi.org/10.1182/blood.v126.23.3422.3422.
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Abstract Integrin-mediated adhesion of lymphocytes to antigen presenting cells (APCs) is a critical event linking innate and adaptive immunity. Integrins function as bidirectional receptors and can transmit signals from both sides of the plasma membrane, a property referred to as inside-out and outside-in signaling. Lymphocyte adhesion to APC is mainly accomplished through the principle adhesion molecule on the lymphocyte surface, the lymphocyte functional antigen 1 (LFA-1), which binds to intercellular adhesion molecule 1 (ICAM-1) on the surface of APCs. In order to mediate its function, LFA-1 must be activated via a process, which results in conformation changes of the receptor that extends the ectodomains of the α and β chains leading to a high affinity state. Among the few signaling molecules that have been implicated in integrin activation in hematopoietic cells are the small GTPase Rap1A (thereafter named Rap1) and its downstream effectors RapL and RIAM. In response to Rap1-GTP, RapL regulates LFA-1 activation by interacting with the integrin α chain, whereas RIAM mediates recruitment of talin to the cytoplasmic tail of the β chain leading to its conformational change to the high affinity state. To understand the role of Rap1 in T cell responses we generated transgenic (Tg) mice that selectively express the active, GTP-bound Rap1 mutant Rap1E63 in mature T cells. Rap1E63-Tg and littermate control mice had no statistically significant difference in absolute thymocyte numbers and differentiation profiles. In contrast, in peripheral lymphoid organs, Rap1E63-Tg mice had a significant reduction in total T cells but a 4-fold increase in the CD4+ CD103+ T cell fraction. CD103 (also known as αEβ7 integrin) defines a subset of peripherally generated Treg with potent suppressive function. TGF-β is the strongest stimulus for induction of CD103 (αEβ7). To examine whether Rap1-GTP can affect TGF-β-mediated signaling in T cells, we used stable Jurkat T cell lines expressing GTP-bound Rap1 mutant, Rap1E63, or Jurkat T cell lines in which the endogenous Rap1 was depleted by shRNA (Rap1-KD), and also primary T cells from Rap1E63-Tg mice and Rap1-KO mice. After interaction with two membrane-bound receptors, TGF-βRI and II, TGF-β propagates downstream signaling via the Smad family transcription factors. Incubation of Rap1E63 Jurkat T cells with TGF-β resulted in enhanced and sustained phosphorylation of Smad2 and Smad3, which was observed with very low concentrations of TGF-β that were incapable of inducing detectable phosphorylation of Smads in control Jurkat T cells. In contrast, diminished level and duration of Smad2 and Smad3 phosphorylation was observed in Rap1-KD Jurkat T cells. Similar patterns of responses to those observed in Rap1E63 Jurkat T cells and in Rap1-KD Jurkat T cells were observed in primary mouse T cells isolated from Rap1E63-Tg mice and Rap1-KO mice, respectively. To investigate whether the LFA-1 integrin α and/or β chain had an active role in the enhanced TGF-β-mediated signaling in the presence of Rap1-GTP, we used Rap1E63 Jurkat T cells in which RapL or RIAM were depleted by shRNA (Rap1E63/RapL-KD and Rap1E63/RIAM-KD) because these adaptors selectively regulate the LFA-1 α and the LFA-1 β chain, respectively, downstream of Rap1-GTP. Although in Rap1E63/RapL-KD cells the enhanced TGF-β-induced Smad3 phosphorylation remained unaffected, in Rap1E63/RIAM-KD cells the enhanced TGF-β-induced Smad3 phosphorylation was abrogated. To investigate the biological relevance of these observations, we used T cells from Rap1E63-Tg mice crossed with mice deficient for the LFA-1 α chain. TGF-β resulted in enhanced Smad3 phosphorylation in T cells from Rap1E63-Tg/LFA1-a KO mice similarly to T cells from Rap1E63-Tg mice, indicating that this effect was not dependent on the activation of LFA-1 α chain. In contrast, T cells from RIAMflox/flox -Lck-Cre mice, in which activation of the LFA-1 β chain is impaired, displayed abrogated activation of Smad3 in response to TGF-β. Our data reveal a novel mechanism by which Rap1 regulates T cell responses via outside-in integrin signaling and may have important implications on TGF-β-mediated T cell homeostasis, differentiation and immune quiescence. Disclosures No relevant conflicts of interest to declare.
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Pfeifer, Christian G., Alexandra Karl, Arne Berner, Johannes Zellner, Paul Schmitz, Markus Loibl, Matthias Koch, Peter Angele, Michael Nerlich, and Michael B. Mueller. "Expression of BMP and Actin Membrane Bound Inhibitor Is Increased during Terminal Differentiation of MSCs." Stem Cells International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/2685147.
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Chondrogenic differentiating mesenchymal stem cells (MSCs) are mimicking embryonal endochondral ossification and become hypertrophic. BMP (bone morphogenetic protein) and Activin Membrane Bound Inhibitor (BAMBI) is a pseudoreceptor that regulates the activity of transforming growth factor-β(TGF-β) and BMP signalling during chondrogenesis. Both TGF-βand BMP signalling are regulators of chondrogenic cell differentiation. Human bone marrow derived MSCs were chondrogenically predifferentiated in aggregate culture for 14 days. Thereafter, one group was subjected to hypertrophy enhancing media conditions while controls were kept in chondrogenic medium until day 28. Histological evaluation, gene expression by PCR, and Western blot analysis were carried out at days 1, 3, 7, 14, 17, 21, and 28. A subset of cultures was treated with the BMP inhibitor Noggin to test for BMP dependent expression of BAMBI. Hypertrophic differentiated pellets showed larger cells with increased collagen 10 and alkaline phosphatase staining. There was significantly increased expression of BAMBI on gene expression and protein level in hypertrophic cultures compared to the chondrogenic control and increased BMP4 gene expression. Immunohistochemistry showed intense staining of BAMBI in hypertrophic cells. BAMBI expression was dose-dependently downregulated by Noggin. The pseudoreceptor BAMBI is upregulated upon enhancement of hypertrophy in MSC chondrogenic differentiation by a BMP dependent mechanism.
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Bandura-Morgan, Laura, Esma Yolcu, Hong Zhao, Shravan Madireddi, and Haval Shirwan. "SA-FasL-Induced Localized Allotolerance to Pancreatic Islets Is Mediated by Phagocytes/TGF-β Axis (145.6)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 145.6. http://dx.doi.org/10.4049/jimmunol.184.supp.145.6.
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Abstract We recently showed that pancreatic islets engineered to display on their surface a recombinant SA-FasL protein induce robust localized tolerance. Tolerance was initiated by FasL-induced alloreactive T cell apoptosis and sustained by Treg cells. We herein tested if tolerance induction involves phagocytes engulfing T cells apoptotic bodies as a means of regulation. C57BL/6 mice were transplanted with BALB/c SA-FasL-islets with the transient use of rapamycin given on the day of Tx daily for 15 days. The role of phagocytes and TGF-β in the induced tolerance was tested by using clodronate-loaded liposomes depletion and an Ab to TGF-β. Depletion of phagocytes using clodronate-loaded liposomes one day prior to Tx resulted in prompt rejection of SA-FasL-engineered islets (n=7). Similarly, in vivo blockade of TGF-β early (day 0, n=5), but not late (>100 days, n=5), postTx resulted in acute rejection of long-term allogeneic SA-FasL-islets. Immunohistochemical analysis revealed that only SA-FasL-engineered islets scored positive for TGF-β and have more macrophages localized in the periphery of islet as compared with SA control. In in vitro cultures, we demonstrated that T cells undergoing SA-FasL-mediated apoptosis expressed membrane-bound TGF-β and these cells were engulfed by macrophages. These data suggest that phagocytosis of apoptotic bodies by phagocytes leads to the secretion of TGF-β, which in turn may facilitate the induction of Treg cells that maintain tolerance.
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Hauri-Hohl, Mathias M., Saulius Zuklys, Marcel P. Keller, Lukas T. Jeker, Thomas Barthlott, Anne M. Moon, Jürgen Roes, and Georg A. Holländer. "TGF-β signaling in thymic epithelial cells regulates thymic involution and postirradiation reconstitution." Blood 112, no. 3 (August 1, 2008): 626–34. http://dx.doi.org/10.1182/blood-2007-10-115618.
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Abstract The thymus constitutes the primary lymphoid organ responsible for the generation of naive T cells. Its stromal compartment is largely composed of a scaffold of different subsets of epithelial cells that provide soluble and membrane-bound molecules essential for thymocyte maturation and selection. With senescence, a steady decline in the thymic output of T cells has been observed. Numeric and qualitative changes in the stromal compartment of the thymus resulting in reduced thymopoietic capacity have been suggested to account for this physiologic process. The precise cellular and molecular mechanisms underlying thymic senescence are, however, only incompletely understood. Here, we demonstrate that TGF-β signaling in thymic epithelial cells exerts a direct influence on the cell's capacity to support thymopoiesis in the aged mouse as the physiologic process of thymic senescence is mitigated in mice deficient for the expression of TGF-βRII on thymic epithelial cells. Moreover, TGF-β signaling in these stromal cells transiently hinders the early phase of thymic reconstitution after myeloablative conditioning and hematopoietic stem cell transplantation. Hence, inhibition of TGF-β signaling decelerates the process of age-related thymic involution and may hasten the reconstitution of regular thymopoiesis after hematopoietic stem cell transplantation.
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Verma, Amit, Tony A. Navas, Jing Ying, Aaron N. Nguyen, Perry Pahanish, Mahesh Seetharam, Irene Kerr, et al. "SD-208, a Novel Transforming Growth Factor Beta Receptor I Kinase Inhibitor, Can Stimulate Hematopoiesis in Myelodysplastic Syndrome Progenitors." Blood 106, no. 11 (November 16, 2005): 3448. http://dx.doi.org/10.1182/blood.v106.11.3448.3448.
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Abstract Transforming Growth Factor β (TGF-β) is a myelosuppressive cytokine that has been implicated in the ineffective hematopoiesis seen in myelodysplastic syndromes (MDS). Overactivation of TGF-β signaling in this disease was demonstrated immunohistochemically by significantly higher nuclear SMAD2 phosphorylation observed in 20 MDS bone marrows when compared with 7 non MDS anemic controls (P < 0.0001, 2 Tailed T Test, Image Pro Plus software). This data along with high levels of membrane-bound and plasma TGF-β observed in MDS patients in previous studies support the development of therapeutics targeting the TGF-β signaling pathways in this disease. SD-208 is a novel, potent and specific inhibitor of TGF-β Receptor I (TGFβ-RI) kinase. We demonstrate that SD-208 blocks the phosphorylation of SMAD2 in hematopoietic progenitors which are at the colony forming unit-erythroid (CFU-E) stage of differentiation. SD-208 also abrogates the G0/G1 cell cycle arrest induced by TGF-β in bone marrow progenitors. SD-208 treatment leads to reversal of the myelosuppressive effects of TGF-β on erythroid and myeloid colony formation from primary human CD34+ cells. Selectivity of SD-208 in inhibiting TGF-β-mediated effects on hematopoiesis was supported by similar results observed with siRNAs targeting SMAD2, a major component of the TGF-b signaling pathway. Finally, the efficacy of SD-208 in MDS was evaluated by treating bone marrow mononuclear cells from 15 patients with early low grade MDS. SD-208 treatment led to dose-dependent increases in erythroid and myeloid colonies after 14 days of in vitro culture. The effect was most notable in patients with high levels of activated SMAD-2, as assessed by immunohistochemical staining of bone marrow biopsies. Stimulation of hematopoiesis in MDS-derived marrow culture by SD-208 demonstrates a novel concept and potential therapeutic role for TGFβ-RI inhibition in this disease. Supported by VISN-17 grant, Harris Methodist Foundation Grant and ASCO YIA to AV
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Greulich, Benjamin M., John Pawlak, John Post, Elena Karas, and Gerard Blobe. "Abstract 6964: Regulation of TGF-β signaling via a novel TβRIII sheddase." Cancer Research 84, no. 6_Supplement (March 22, 2024): 6964. http://dx.doi.org/10.1158/1538-7445.am2024-6964.
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Abstract In a normal cell, TGF-β signaling serves as a tumor suppressor by reducing proliferation and promoting apoptosis. Paradoxically, the function of TGF-β signaling reverses in a cancer cell and begins to promote oncogenic pathways such as proliferation, survival, evasion of the immune system, and epithelial to mesenchymal transition (EMT). This has made TGF-β signaling a very attractive therapeutic target for a wide variety of human carcinomas. As a result, many small molecule inhibitors of TGF-β signaling have been developed, but none have achieved FDA approval for use in human cancers due to the deleterious effects of inhibiting TGF-β responsiveness in normal cells. In effort to overcome this obstacle, we aim to restore the normal biological mechanisms that regulate TGF-β signaling. Specifically, the membrane bound co-receptor TβRIII can be proteolytically cleaved and shed from the membrane, resulting in an extracellular protein capable of binding and sequestering TGF-β ligand. This decoupling of ligand binding from the receptor allows TβRIII to suppress signaling. TβRIII shedding decreases TGF-β mediated oncogenic phenotypes such as migration and metastasis in multiple cancer types. However, this shedding is often lost in cancer. Therefore, restoration of TβRIII shedding could be a viable therapeutic approach for multiple cancer types. One potential mechanism for the loss of shedding is the negative regulation of the protease responsible for shedding (sheddase). However, the identity of the sheddase still remains unknown. Here, our goal is to identify the sheddase and uncover regulatory mechanisms that could be leveraged to restore TβRIII shedding in cancer. To achieve this goal, a library of protease CRISPR knockout viruses was screened to determine which proteases have an effect on shedding. The quantity of TβRIII shed into the cell culture media was measured via ELISA for each of these CRISPR knockout cell lines, and the candidates with the largest reduction of shedding were retained for further investigation. The list of candidates was further screened in silico via gene set enrichment analysis of human patient data against a TGF-β signaling gene set signature. Only the candidates demonstrating a negative correlation between sheddase candidate expression and TGF-β signaling activity were studied further. To further validate these candidate sheddases, knockdown and overexpression cell lines were created and characterized. Overexpression of the most promising candidate reduced TGF-β mediated phenotypes such as migration and invasion, while knockdown of this candidate increased the same phenotypes. Knockdown also increased expression of TGF-β and EMT markers. Importantly, these effects of sheddase knockdown were neutralized in the presence of the TGF-β inhibitor galunisertib or when the cells were rescued with exposure to purified soluble TβRIII, indicating the effects are mediated through TβRIII shedding. Citation Format: Benjamin M. Greulich, John Pawlak, John Post, Elena Karas, Gerard Blobe. Regulation of TGF-β signaling via a novel TβRIII sheddase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6964.
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Guizzardi, Stefano, Giuseppe Pedrazzi, and Carlo Galli. "Low Frequency Electromagnetic Fields Might Increase the Effect of Enamel Matrix Derivative on Periodontal Tissues." Applied Sciences 11, no. 22 (November 15, 2021): 10758. http://dx.doi.org/10.3390/app112210758.
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Periodontal regeneration is a complex goal, which is commonly pursued with a combination of surgical techniques, biomaterials, and bioactive compounds. One such compound is enamel matrix derivative (EMD), a medical substance that is extracted from porcine tooth germs and which contains several protein fractions with BMP- and TGF-β-like action. Activation of TGF-β signaling is required for EMD activity on cells and tissues, and a growing body of evidence indicates that EMD largely relies on this pathway. As low frequency electromagnetic fields (EMFs) have long been investigated as a tool to promote bone formation and osteoblast activity, and because recent studies have reported that the effects of EMFs on cells require primary cilia, by modulating the presence of membrane-bound receptors (e.g., for BMP) or signal mediators, it can be hypothesized that the application of EMFs may increase cell sensitivity to EMD: as TGFBR receptors have also been identified on primary cilia, EMFs could make cells more responsive to EMD by inducing the display of a higher number of receptors on the cellular membrane.
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Lynch, M. A., T. A. Petrel, H. Song, T. J. Knobloch, B. C. Casto, D. Ramljak, L. M. Anderson, et al. "Responsiveness to Transforming Growth Factor-β (TGF-β)-Mediated Growth Inhibition Is a Function of Membrane-Bound TGF-β Type II Receptor in Human Breast Cancer Cells." Gene Expression 9, no. 4 (April 1, 2001): 157–71. http://dx.doi.org/10.3727/000000001783992560.
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Ostroukhova, Marina, Carole Seguin-Devaux, Timothy B. Oriss, Barbara Dixon-McCarthy, Liyan Yang, Bill T. Ameredes, Timothy E. Corcoran, and Anuradha Ray. "Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3." Journal of Clinical Investigation 114, no. 1 (July 1, 2004): 28–38. http://dx.doi.org/10.1172/jci200420509.
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Eill, Elizabeth, and Steven M. Taffet. "IL-10 and TGF- β differentially regulate gap junction formation and membrane transfer in macrophages and macrophage-like cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 58.19. http://dx.doi.org/10.4049/jimmunol.202.supp.58.19.
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Abstract In macrophages, the expression and regulation of the gap junction protein connexin43 (Cx43) is poorly understood. Here we demonstrate that inflammatory and anti-inflammatory mediators differentially regulate gap junction plaque formation in primary bone marrow-derived macrophages (BMDMs) and the macrophage-like cell line RAW264.7. RAW264.7 macrophage-like cells were transfected with GFP-tagged Cx43 to visualize Cx43 trafficking. LPS, an inflammatory mediator, is a potent inducer of Cx43 in BMDMs and RAW264-Cx43-GFP but demonstrates limited trafficking into gap junction plaques. Interestingly, the further addition of IL-10, an anti-inflammatory cytokine, resulted in no difference in protein expression but significantly increased gap junction plaque formation. In contrast to IL-10, the addition of TGF-β (beta) decreased Cx43 protein levels and prevented gap junction plaque formation. We utilized a dye transfer assay to assess gap junction intracellular communication. We could not demonstrate any channel-associated transfer of an intracellular dye, calcein. Uniquely, macrophages were observed transferring endosome-like particles containing membrane between cells as visualized with the membrane-bound dye DiI. This appeared to be through long tube-like structures, possibly tunneling nanotubes. This effect was enhanced with IL-10 treatment and decreased with TGF-β. These results suggest that IL-10 and TGF-β differentially regulate Cx43 plaque formation and that this corresponds to changes in the transfer of cellular components in a gap junction channel-independent way. Overall these results suggest a complex and novel regulation of Cx43 gap junction formation in macrophages and macrophage-like cells.
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Patsoukis, Nikolaos, Lequn Li, and Vassiliki A. Boussiotis. "Rap1-GTP Augments Activation of Smad and p38 Mediated Signaling Downstream of TGF-β Receptor In T Lymphocytes." Blood 116, no. 21 (November 19, 2010): 956. http://dx.doi.org/10.1182/blood.v116.21.956.956.
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Abstract Abstract 956 Rap1A, a member of the Ras superfamily, was discovered as a gene product that reverted K-Ras-induced transformation. Although it was initially thought that Rap1A (thereafter referred to as Rap1) opposes Ras-induced transformation by competing for common downstream effector(s), it has now become apparent that Ras and Rap1 proteins operate in different signaling networks and mediate distinct functions. In lymphocytes Rap1 is activated by BCR and TCR mediated signals and is involved in inside-out activation of integrins. To understand the role of Rap1 in T cell responses we generated transgenic (Tg) mice that express the active Rap1 mutant Rap1E63 in T cells. Rap1E63-Tg and littermate control mice had no statistically significant difference in absolute thymocyte numbers and differentiation profiles of double positive and single positive thymocytes. In contrast to thymocyte numbers, Rap1E63-Tg mice had reduced T cell numbers in peripheral lymphoid organs. In peripheral lymph nodes and spleen, the total T cell numbers were decreased to approximately one third to one forth of those in littermate controls. Strikingly, Rap1E63-Tg mice had a 4-fold increase in the CD4+CD103+ T cell fraction in spleens and lymph nodes compared to their littermate controls. CD103 defines a subset of peripherally generated Treg with potent suppressive function. CD4+CD103+ Treg cells in RapE63-Tg mice expressed CD45RBlow, CD44high, CD54high, CD62Llow and LFA-1high, findings consistent with an effector memory phenotype. TGF-β is the strongest stimulus for induction of CD103 expression. To examine whether Rap1 affected TGF-β-mediated signaling in T cells, we used stable Jurkat T cell lines expressing Rap1E63, Jurkat T cell lines, in which endogenous Rap1 was depleted by shRNA (Rap1-KD), and primary T cells from Rap1E63-Tg mice and Rap1-KO mice. TGF-β signaling involves the interaction of two membrane-bound receptors, TGF-βRI and II. TGF-β binds the exracellular domain of TGF-βRII, which then recruits TGF-βRI resulting in transphosphorylation. TGF-βRI activation propagates downstream signaling via the Smad family proteins Smad2 and Smad3 and also via p38 MAPK, in a Smad-independent manner. Incubation of Rap1E63 Jurkat T cells with TGF-β resulted in enhanced and sustained phosphorylation of Smad2 and Smad3, which was observed with very low concentrations of TGF-β that were incapable of inducing detectable phosphorylation of Smad2 or Smad3 in control cells. In contrast, diminished level and duration of Smad2 and Smad3 phosphorylation was observed in Rap1-KD Jurkat cells. Activation of p38 downstream of TGF-βRI displayed a dramatically augmented and sustained induction, whereas the opposite effect was observed in Rap1-KD cells. Similar patterns of responses to those observed in Rap1E63 Jurkat T cells and in Rap1-KD cells were observed in primary mouse T cells isolated from Rap1E63-Tg mice and Rap1 deficient mice, respectively. Assessment of TGF-β binding on TGF-β surface receptors by using biotinylated TGF-β revealed that Rap1E63 expressing cells displayed significantly enhanced TGF-β binding compared to their relevant controls, whereas reduced TGF-β binding was observed in Rap1 deficient cells. These results indicate that active Rap1 modulates TGF-β receptor binding and enhances TGF-β mediated signaling, gene transcription, and functional outcome. Our data reveal a novel and unexpected mechanism by which Rap1 regulates T cell responses that may have important implications on TGF-β-mediated T cell homeostasis and maintenance of immune quiescence. Disclosures: No relevant conflicts of interest to declare.
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Wang, Hong-Min, Zhe Zhou, Jie Miao, Bo Zhu, Xiao-Qiu Dai, Qiao Zhong, Fang-Yuan Gong, and Xiao-Ming Gao. "Membrane Bound CRT Fragment Accelerates Tumor Growth of Melanoma B16 Cell In Vivo through Promoting M2 Polarization via TLR4." Journal of Immunology Research 2022 (October 6, 2022): 1–12. http://dx.doi.org/10.1155/2022/4626813.
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Calreticulin (CRT) is a major calcium-binding luminal resident protein on the endoplasmic reticulum that can also be released extracellular as well as anchored on surface of cells. Previously, we demonstrated that soluble recombinant CRT fragment 39-272 (CRT/39-272) exhibited potent immunostimulatory effects as well as immunoregulation effects on immune cells. Here, we constructed stable B16 melanoma cell lines expressing recombinant CRT/39-272 on the membrane (B16-tmCRT/39-272) to investigate the roles of cell surface CRT on tumor progression. We found that B16-tmCRT/39-272 cells subcutaneously inoculated into C57BL/6 mice exhibited stronger tumorigenicity than the B16-EGFP control cells. The tumor associated macrophages infiltrated in tumors were mainly M2 phenotype. Regulatory T cells (Tregs) were also expanded more in bearing mice. Consistent with the in vivo results, B16-tmCRT/39-272 promoted macrophage polarization toward F4/80+CD206+ M2 macrophages and promoted transforming growth factor beta (TGF-β) secretion in vitro, which could promote naïve CD4+T cell differentiation into Tregs. These results imply that the tmCRT/39-272 could accelerate tumor development by enhancing M2 macrophage polarization to induce TGF-β secretion, and then promoted Treg differentiation in the tumor microenvironment. Our data may provide useful clues for better understanding of the potentiating roles of CRT in tumorigenesis.
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Hyytiäinen, Marko, and Jorma Keski-Oja. "Latent TGF-β binding protein LTBP-2 decreases fibroblast adhesion to fibronectin." Journal of Cell Biology 163, no. 6 (December 22, 2003): 1363–74. http://dx.doi.org/10.1083/jcb.200309105.
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We have analyzed the effects of latent TGF-β binding protein 2 (LTBP-2) and its fragments on lung fibroblast adhesion. Quantitative cell adhesion assays indicated that fibroblasts do not adhere to full-length LTBP-2. Interestingly, LTBP-2 had dominant disrupting effects on the morphology of fibroblasts adhering to fibronectin (FN). Fibroblasts plated on LTBP-2 and FN substratum exhibited less adherent morphology and displayed clearly decreased actin stress fibers than cells plated on FN. These cells formed, instead, extensive membrane ruffles. LTBP-2 had no effects on cells adhering to collagen type I. Fibroblasts adhered weakly to the NH2-terminal fragment of LTBP-2. Unlike FN, this fragment did not augment actin stress fiber formation. Interestingly, the adhesion-mediating and cytoskeleton-disrupting effects were localized to the same NH2-terminal proline-rich region of LTBP-2. LTBP-2 and its antiadhesive fragment bound to FN in vitro, and the antiadhesive fragment associated with the extracellular matrix FN fibrils. These observations reveal a potentially important role for LTBP-2 as an antiadhesive matrix component.
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Payet, Melissa, Franck Ah-Pine, Xavier Guillot, and Philippe Gasque. "Inflammatory Mesenchymal Stem Cells Express Abundant Membrane-Bound and Soluble Forms of C-Type Lectin-like CD248." International Journal of Molecular Sciences 24, no. 11 (May 31, 2023): 9546. http://dx.doi.org/10.3390/ijms24119546.
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CD248 (endosialin) belongs to a glycoprotein family that also includes thrombomodulin (CD141), CLEC14A, and CD93 (AA4) stem cell markers. We analyzed the regulated expression of CD248 in vitro using skin (HFFF) and synovial (FLS) mesenchymal stem cell lines, and in fluid and tissue samples of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. Cells were incubated with either rhVEGF165, bFGF, TGF-β1, IL1-β, TNF-α, TGFβ1, IFN-γ, or PMA (Phorbol ester). There was no statistically significant change in membrane expression. A soluble (s) form of cleaved CD248 (sCD248) was detected after cell treatment with IL1-β and PMA. Matrix metalloprotease (MMP) MMP-1 and MMP-3 mRNAs were significantly up-regulated by IL1-β and PMA. A broad MMP inhibitor blocked the release of soluble CD248. In RA synovial tissue, we identified CD90+ perivascular MSCs double-stained for CD248 and VEGF. High sCD248 levels were detected in synovial fluid from RA. In culture, subpopulations of CD90+ CD14− RA MSCs were either identified as CD248+ or CD141+ cells but CD93−. CD248 is abundantly expressed by inflammatory MSCs and shed in an MMP-dependent manner in response to cytokines and pro-angiogenic growth factors. Both membrane-bound and soluble CD248 (acting as a decoy receptor) may contribute to RA pathogenesis.
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Boyiadzis, Michael, Miroslaw Szczepanski, and Theresa Whiteside. "Membrane Associated TGF-β1 on Leukemia Blast-Derived Microvesicles In Sera of Acute Myeloid Leukemia Patients Suppresses NK Cell Function." Blood 116, no. 21 (November 19, 2010): 502. http://dx.doi.org/10.1182/blood.v116.21.502.502.
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Abstract Abstract 502 Natural killer (NK) cell cytotoxicity in patients with acute myeloid leukemia (AML) is significantly decreased relative to that in normal controls (NC). TGF-β1 is a potent inhibitor of NK cell cytotoxicity. We considered the possibility that suppression of NK cell activity in AML patients is mediated by leukemia blast-derived microvesicles (MV) via TGF-β1. Sera of 19 patients newly diagnosed with AML prior to any treatment were used to isolate MV by ultracentrifugation. MV from AML patients were positive for the blast-associated markers (CD33, CD34, CD117) by flow cytometry and for membrane-associated TGFb-1 in Western blots, whereas neither these markers nor TGFb-1 were detected in MV from NC. The protein content of blast-derived MV was higher (p<0.001) than that of MV isolated from sera of 25 NC (75μ g±12/mL vs 1.2μ g±0.4/mL). To evaluate MV-mediated NK cell suppression, NK cells obtained from NC were co-incubated with MV isolated from patients' sera. A significant decrease (p<0.002) in NK cell cytotoxicity (2412 LU pre- vs 1640 LU post co-incubation) was accompanied by a concomitant decrease (p<0.004) in the NK-cell activating receptor, NKG2DR, expression levels. To determine whether MV-associated TGF-β1 was responsible for these adverse effects of MV on NK cells, neutralizing anti-TGF-β1 mAb was added to the co-cultures. This mAb significantly abrogated MV-mediated inhibition of NK cell cytotoxicity and down-regulation of the NKG2DR expression level. We next measured the plasma concentrations of TGF-β1 in AML patients and NC. The mean ± SD plasma concentration of TGF-β1 was 2,600 pg/mL ± 2,500 in patients vs. 101 pg/mL ± 55 in NC (p<0.0001). The use of urea, which disassociated membrane-bound TGF-β1 in MV, resulted in a significant increase of the measured TGF-β1 levels (mean 13,700 pg/mL ± 9,800) only in the sera of AML patients but not in the sera of NC. To determine whether the SMAD pathway used by the TGF-β family members is involved in the MV-NK cell interactions, we co-incubated NK cells with MV isolated from sera of AML patients. These MV induced SMAD phosphorylation in NK cells. The addition of anti-TGF-β1 mAbs to the co-culture inhibited SMAD phosphorylation but did not alter expression of the SMAD protein itself. These data provide evidence for a novel mechanism responsible for down-regulation of NK cell activity and NKG2DR expression levels by TGF-β1 associated with leukemia blast-derived MV in AML patients. Disclosures: No relevant conflicts of interest to declare.
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Prud’homme, Gérald J., and Qinghua Wang. "Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging." Cells 13, no. 17 (August 24, 2024): 1413. http://dx.doi.org/10.3390/cells13171413.
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The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer’s disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, s-Klotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.
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Cohen, Margo P., Fuad N. Ziyadeh, Gregory T. Lautenslager, Jonathan A. Cohen, and Clyde W. Shearman. "Glycated albumin stimulation of PKC-β activity is linked to increased collagen IV in mesangial cells." American Journal of Physiology-Renal Physiology 276, no. 5 (May 1, 1999): F684—F690. http://dx.doi.org/10.1152/ajprenal.1999.276.5.f684.
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Albumin modified by Amadori-glucose adducts induces coordinate increases in the expression of extracellular matrix proteins, transforming growth factor (TGF)-β1, and the TGF-β type II receptor in glomerular mesangial cells. Because activation of protein kinase C (PKC) accompanies the increased mesangial cell expression of matrix proteins and TGF-β1 induced by high ambient glucose, we postulated that glycated albumin (GA) modulates PKC activity and that PKC participates in mediating the GA-induced stimulation of matrix production. To test this hypothesis, we examined the effects of PKC inhibitors on collagen type IV production by mouse or rat mesangial cells incubated with GA, and the influence of GA on PKC activity in these cells. Increased collagen type IV production evoked by GA in 5.5 and 25 mM glucose in mouse mesangial cells was prevented by both general (GF-109203X) and β-specific (LY-379196) PKC inhibitors. Total PKC activity, measured by phosphorylation of a PKC-specific substrate, increased with time after exposure of rat mesangial cells to GA compared with the nonglycated, glucose-free counterpart. GA caused an increase in PKC-β1 membrane-bound fraction and in total PKC activity in media containing physiological (5.5 mM) glucose concentrations in rat mesangial cells, confirming that the glucose-modified protein, and not a “hyperglycemic” milieu, was responsible. The findings indicate that Amadori-modified albumin stimulates mesangial cell PKC activity, and that activation of the PKC-β isoform is linked to the stimulation of collagen type IV production.
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Zhang, Minggang, Sheng Xu, Yanmei Han, and Xuetao Cao. "Apoptotic cells attenuate fulminant hepatitis by priming Kupffer cells to produce interleukin-10 through membrane-bound TGF-β." Hepatology 53, no. 1 (December 7, 2010): 306–16. http://dx.doi.org/10.1002/hep.24029.
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Ghiringhelli, François, Cédric Ménard, Magali Terme, Caroline Flament, Julien Taieb, Nathalie Chaput, Pierre E. Puig, et al. "CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner." Journal of Experimental Medicine 202, no. 8 (October 17, 2005): 1075–85. http://dx.doi.org/10.1084/jem.20051511.
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Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.
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Tang, Jiaqi, Cody Gifford, Rohan Samarakoon, and Paul Higgins. "Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression." Cancers 10, no. 6 (May 25, 2018): 159. http://dx.doi.org/10.3390/cancers10060159.
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The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.
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Hsu, Hsiang-Hao, Aline Yen Ling Wang, Charles Yuen Yung Loh, Ashwin Alke Pai, and Huang-Kai Kao. "Therapeutic Potential of Exosomes Derived from Diabetic Adipose Stem Cells in Cutaneous Wound Healing of db/db Mice." Pharmaceutics 14, no. 6 (June 6, 2022): 1206. http://dx.doi.org/10.3390/pharmaceutics14061206.
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(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in vivo mechanistic basis by which diabetic ASC-Exo enhance cutaneous wound healing in a diabetic mouse model. (2) Methods: Topically applied exosomes could efficiently target and preferentially accumulate in wound tissue, and the cellular origin, ASC or dermal fibroblast (DFb), has no influence on the biodistribution pattern of exosomes. In vivo, full-thickness wounds in diabetic mice were treated either with ASC-Exo, DFb-Exo, or phosphate-buffered saline (PBS) topically. ASC-Exo stimulated wound healing by dermal cell proliferation, keratinocyte proliferation, and angiogenesis compared with DFb-Exo and PBS-treated wounds. (3) Results: Diabetic ASC-Exo stimulated resident monocytes/macrophages to secrete more TGF-β1 and activate the TGF-β/Smad3 signaling pathway. Fibroblasts activated by TGF-β1containing exosomes from ASCs initiate the production of TGF-β1 protein in an autocrine fashion, which leads to more proliferation and activation of fibroblasts. TGF-β1 is centrally involved in diabetic ASC-Exo mediated cellular crosstalk as an important early response to initiating wound regeneration. (4) Conclusions: The application of diabetic ASC-Exo informs the potential utility of a cell-free therapy in diabetic wound healing.
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Devocelle, Aurore, Lola Lecru, Hélène François, Christophe Desterke, Cindy Gallerne, Pierre Eid, Oberlin Estelle, Bruno Azzarone, and Julien Giron-Michel. "Inhibition of TGF-β1 Signaling by IL-15: A Novel Role for IL-15 in the Control of Renal Epithelial-Mesenchymal Transition: IL-15 Counteracts TGF-β1-Induced EMT in Renal Fibrosis." International Journal of Cell Biology 2019 (July 7, 2019): 1–15. http://dx.doi.org/10.1155/2019/9151394.
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Renal tubulointerstitial fibrosis is the final common pathway in end-stage renal disease and is characterized by aberrant accumulation of extracellular matrix (ECM) components secreted by myofibroblasts. Tubular type 2 EMT, induced by TGF-β, plays an important role in renal fibrosis, by participating directly or indirectly in myofibroblasts generation. TGF-β1-induced apoptosis and fibrosis in experimental chronic murine kidney diseases are concomitantly associated with an intrarenal decreased expression of the IL-15 survival factor. Since IL-15 counteracts TGF-β1 effects in different cell models, we analyzed whether (1) human chronic inflammatory nephropathies evolving towards fibrosis could be also characterized by a weak intrarenal IL-15 expression and (2) IL-15 could inhibit epithelial-mesenchymal transition (EMT) and excess matrix deposition in human renal proximal tubular epithelial cells (RPTEC). Our data show that different human chronic kidney diseases are characterized by a strong decreased expression of intrarenal IL-15, which is particularly relevant in diabetic nephropathy, in which type 2 tubular EMT plays an important role in fibrosis. Moreover, primary epithelial tubular cultures deprived of growth supplements rapidly produce active TGF-β1 inducing a “spontaneous” EMT process characterized by the loss of membrane-bound IL-15 (mbIL-15) expression. Both “spontaneous” EMT and recombinant human (rh) TGF-β1-induced EMT models can be inhibited by treating RPTEC and HK2 cells with rhIL-15. Through a long-lasting phospho-c-jun activation, IL-15 inhibits rhTGF-β1-induced Snail1 expression, the master inducer of EMT, and blocks TGF-β1-induced tubular EMT and downstream collagen synthesis. In conclusion, our data suggest that intrarenal IL-15 could be a natural inhibitor of TGF-β in human kidney able to guarantee epithelial homeostasis and to prevent EMT process. Thus, both in vivo and in vitro an unbalance in intrarenal IL-15 and TGF-β1 levels could render RPTEC cells more prone to undergo EMT process. Exogenous IL-15 treatment could be beneficial in some human nephropathies such as diabetic nephropathy.
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Chonov, Dimitur Chavdarov, Maria Magdalena Krasimirova Ignatova, Julian Rumenov Ananiev, and Maya Vladova Gulubova. "IL-6 Activities in the Tumour Microenvironment. Part 1." Open Access Macedonian Journal of Medical Sciences 7, no. 14 (July 20, 2019): 2391–98. http://dx.doi.org/10.3889/oamjms.2019.589.
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The predominant role of IL-6 in cancer is its key promotion of tumour growth. IL-6 binds IL-6 receptor (IL-6R) and the membrane-bound glycoprotein gp130. The complex I-6/IL-6R/gp130 starts the Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3) or JAK/STAT3 pathway. IL-6R exits in two forms: a membrane-bound IL-6Rα subunit (mIL-6R) that participates in classic signalling pathway and soluble IL-6R subunit (sIL-6R) engaged in trans-signalling. The pro-tumour functions of IL-6 are associated with STAT3, a major oncogenic transcription factor that triggers up-regulation of target genes responsible for tumour cell survival. IL-6 combined with TGF-β induces proliferation of pathogenic Th17 cells. The anti-tumour function of IL-6 is the promotion of anti-tumour immunity. IL-6 trans-signaling contributed to transmigration of lymphocytes in high endothelial venules (HEV). Dendritic cell (DC) secreted IL-6 in the lymph node influences the activation, distribution and polarisation of the immune response. Elevated serum levels of IL-6 and increased expression of IL-6 in tumour tissue are negative prognostic marker for patients’ survival.
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Liu, Cheng, Xiaorong Chen, Ling Yang, Tatiana Kisseleva, David A. Brenner, and Ekihiro Seki. "Transcriptional Repression of the Transforming Growth Factor β (TGF-β) Pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) by Nuclear Factor κB (NF-κB) p50 Enhances TGF-β Signaling in Hepatic Stellate Cells." Journal of Biological Chemistry 289, no. 10 (January 21, 2014): 7082–91. http://dx.doi.org/10.1074/jbc.m113.543769.
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Guo, Chao, Yanying Fan, Alexander Aronov, Qi Zhang, Sombeet Sahu, Mary-Lee Dequéant, Changan Guo, et al. "Abstract 5512: CBLB, CISH and CD70 multiplexed gene knockout with CRISPR/Cas9 enhances cytotoxicity of CD70-CAR NK cells and provides greater resistance to TGF-β for cancer immunotherapy." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5512. http://dx.doi.org/10.1158/1538-7445.am2022-5512.
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Abstract Natural killer (NK) cells provide an attractive platform for development of effective cancer immunotherapies. NK cells are known for their ability to kill tumor cells and do not elicit graft-versus-host disease, making them a potential source of ‘off-the-shelf’ allogeneic cell therapy. NK cells are also amenable to CRISPR genomic engineering to enhance the antitumor activity of NK cells by increasing their cytotoxicity, overcoming suppression within the tumor microenvironment, or promoting their persistence and homing to tumor sites. Cytokine inducible SH2-containing protein (CISH) is a NK cell checkpoint for IL-15 mediated NK survival, proliferation, cytotoxicity, and anti-tumor immunity. The E3 ubiquitin ligase CBLB is also a negative regulator of NK cell function and has been shown to mediate TGF-β sensitivity by downregulating inhibitory SMAD7 in primary T cells. We hypothesized that knockout of both CISH and CBLB would not only improve NK cell effector function and but also render NK cells resistant to TGF-β mediated suppression. In this study, we utilized CRISPR-Cas9 ribonucleoproteins (RNPs) to disrupt CISH and CBLB genes in isolated peripheral blood NK cells from healthy donors. Given that CD70 expression is present on activated NK cells, to target CD70 on renal cell carcinoma (RCC) with CAR NK cells, CD70 was knocked out in NK cells to avoid fratricide. Western blotting, FACS and TIDE/Amplicon NGS Sequencing data confirmed all three genes were successfully disrupted. Then we expanded these edited NK cells by using IL-2 and stimulation using NKSTIM, a modified K562 stimulatory cell line expressing membrane-bound form of IL-15 (mbIL-15) and 4-1BBL. IL-12 and IL-18 were added during expansion to drive memory-like NK cell differentiation. Furthermore, we were able to transduce CRISPR/Cas9 edited NK cells to express a CD70-CAR construct and membrane bound IL-15. CAR expression was assessed by flow cytometry. In vitro cytotoxicity was measured using the IncuCyte S3 live cell analysis system. CD70/CISH/CBLB triple knockout CD70-CAR NK cells could be produced efficiently and exhibited similar persistence as CD70/CISH or CD70/CBLB double knockout CD70-CAR NK cells in culture. Cytotoxicity assays demonstrated that CD70/CISH/CBLB triple knockout CD70-CAR NK cells had greater tumor growth control after multiple rechallenges. In the presence of exogenous TGF-β, CD70/CISH/CBLB triple knockout CD70-CAR NK cells showed greater resistance to TGF-β inhibition of cytotoxicity. In summary, we show CD70/CISH/CBLB triple knockout CD70-CAR NK cells demonstrate enhanced anti-tumor activity against relevant solid tumor cell lines and provide greater resistance to tumor microenvironment inhibition. These data support the further exploration of CD70/CISH/CBLB triple gene knockout CD70 CAR NK cells for clinical application. Citation Format: Chao Guo, Yanying Fan, Alexander Aronov, Qi Zhang, Sombeet Sahu, Mary-Lee Dequéant, Changan Guo, Sushant Karnik, Glenn D. Leary, Chandirasegaran Massilamany, Ivan H. Chan, James B. Trager. CBLB, CISH and CD70 multiplexed gene knockout with CRISPR/Cas9 enhances cytotoxicity of CD70-CAR NK cells and provides greater resistance to TGF-β for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5512.
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Chen, Yongyan, Rui Sun, Xunyao Wu, Min Cheng, Haiming Wei, and Zhigang Tian. "CD4+CD25+ Regulatory T Cells Inhibit Natural Killer Cell Hepatocytotoxicity of Hepatitis B Virus Transgenic Mice via Membrane-Bound TGF-β and OX40." Journal of Innate Immunity 8, no. 1 (June 9, 2015): 30–42. http://dx.doi.org/10.1159/000431150.
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CD4+CD25+ regulatory T cells (Tregs) are involved in the regulation of physiological and pathological hepatic immune responses, but the roles are not well explored in natural killer (NK) cell-mediated liver diseases. In this study, using the NK cell-mediated oversensitive liver injury model of hepatitis B virus transgenic (HBs-Tg) mice triggered by a low dose of concanavalin A, it was observed that an increased number of CD4+CD25+Foxp3+ Tregs were accumulated in the liver, along with the recovery of liver injury. Adoptive transfer of hepatic Tregs from HBs-Tg mice but not wild B6 mice could significantly attenuate the oversensitive liver injury via inhibiting liver accumulation and decreasing NK cell group 2D-mediated activation of NK cells in the recipient HBs-Tg mice. Furthermore, upregulated expression of membrane-bound TGF-β (mTGF-β) and OX40 on hepatic Tregs were demonstrated to account for inhibiting the NK cell-mediated hepatic injury in HBs-Tg mice through cell-cell contact, confirmed by antibody blockade and cell Transwell experiments in vivo and in vitro. Our findings for the first time indicated that CD4+CD25+ Tregs directly suppressed NK cell-mediated hepatocytotoxicity through mTGF-β and OX40/OX40L interaction in a cell-cell contact manner in HBV-associated liver disease.
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Liu, Ning, Toshiaki Makino, Fumiaki Nogaki, Hitoshi Kusano, Katsuo Suyama, Eri Muso, Gisho Honda, Toru Kita, and Takahiko Ono. "Coagulation in the mesangial area promotes ECM accumulation through factor V expression in MsPGN in rats." American Journal of Physiology-Renal Physiology 287, no. 4 (October 2004): F612—F620. http://dx.doi.org/10.1152/ajprenal.00322.2003.
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It is well known that tissue factor starts the extrinsic coagulation pathway, which activates factor X to Xa, and factor V is a membrane-bound potent cofactor for the terminating stage of prothrombin activation by factor Xa. In a previous in vitro study, factor V was induced in cultured mesangial cells by inflammatory stimulation and increased expression of factor V promoted fibrin generation on the cultured mesangial cell surface. We report that extracellular matrix (ECM) accumulation is increased in association with coagulation in the mesangial area through factor V expression in mesangioproliferative glomerulonephritis (MsPGN). Wistar rats were intravenously injected with rabbit anti-rat thymocyte serum accompanied with or without simultaneous injection of rabbit anti-factor V antibody. Time course study in immunohistochemistry revealed that factor V expression was prominent on day 3 and fibrin-related antigen (FRA) deposition, then ECM accumulation, followed from day 3 to day 8. Massive fibronectin depositions and transforming growth factor (TGF)-β expression were also noted in glomeruli from the disease control group, markedly higher than those in the normal group, and these depositions and expressions were significantly decreased in the anti-factor V neutralizing antibody-injected group. Northern blot analysis revealed that factor V mRNA expression was prominent on day 3 and was weak on day 8. Double-labeling experiments revealed the frequent colocalization of α-smooth muscle actin with factor V, FRA, and fibronectin in the same mesangial areas of glomeruli. TGF-β, connective tissue growth factor (CTGF), collagen type IV, and fibronectin mRNA were upregulated in the disease control group, and anti-factor V-neutralizing antibody injection suppressed these mRNA expressions in glomeruli. The present results suggest that ECM components accumulation may progress in accordance with coagulation in the mesangial area through mesangial factor V expression and upregulated expression of TGF-β and CTGF in MsPGN.
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Gregg, Randal K., Renu Jain, Scott J. Schoenleber, Rohit Divekar, J. Jeremiah Bell, Hyun-Hee Lee, Ping Yu, and Habib Zaghouani. "A Sudden Decline in Active Membrane-Bound TGF-β Impairs Both T Regulatory Cell Function and Protection against Autoimmune Diabetes." Journal of Immunology 173, no. 12 (December 7, 2004): 7308–16. http://dx.doi.org/10.4049/jimmunol.173.12.7308.
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Brownlie, Demi, Dahlia Doughty-Shenton, Daniel YH Soong, Colin Nixon, Neil O Carragher, Leo M Carlin, and Takanori Kitamura. "Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β." Journal for ImmunoTherapy of Cancer 9, no. 1 (January 2021): e001740. http://dx.doi.org/10.1136/jitc-2020-001740.
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BackgroundMetastatic breast cancer is a leading cause of cancer-related death in women worldwide. Infusion of natural killer (NK) cells is an emerging immunotherapy for such malignant tumors, although elimination of the immunosuppressive tumor environment is required to improve its efficacy. The effects of this “metastatic” tumor environment on NK cells, however, remain largely unknown. Previous studies, including our own, have demonstrated that metastasis-associated macrophages (MAMs) are one of the most abundant immune cell types in the metastatic tumor niche in mouse models of metastatic breast cancer. We thus investigated the effects of MAMs on antitumor functions of NK cells in the metastatic tumor microenvironment.MethodsMAMs were isolated from the tumor-bearing lung of C57BL/6 mice intravenously injected with E0771-LG mouse mammary tumor cells. The effects of MAMs on NK cell cytotoxicity towards E0771-LG cells were evaluated in vitro by real-time fluorescence microscopy. The effects of MAM depletion on NK cell activation, maturation, and accumulation in the metastatic lung were evaluated by flow cytometry (CD69, CD11b, CD27) and in situ hybridization (Ncr1) using colony-stimulating factor 1 (CSF-1) receptor conditional knockout (Csf1r-cKO) mice. Finally, metastatic tumor loads in the chest region of mice were determined by bioluminescence imaging in order to evaluate the effect of MAM depletion on therapeutic efficacy of endogenous and adoptively transferred NK cells in suppressing metastatic tumor growth.ResultsMAMs isolated from the metastatic lung suppressed NK cell-induced tumor cell apoptosis in vitro via membrane-bound transforming growth factor β (TGF-β) dependent mechanisms. In the tumor-challenged mice, depletion of MAMs increased the percentage of activated (CD69+) and mature (CD11b+CD27–) NK cells and the number of Ncr1+ NK cells as well as NK cell-mediated tumor rejection in the metastatic site. Moreover, MAM depletion or TGF-β receptor antagonist treatment significantly enhanced the therapeutic efficacy of NK cell infusion in suppressing early metastatic tumor outgrowth.ConclusionThis study demonstrates that MAMs are a main negative regulator of NK cell function within the metastatic tumor niche, and MAM targeting is an attractive strategy to improve NK cell-based immunotherapy for metastatic breast cancer.
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Kuhn, Chantal, Rafael Machado Rezende, Hanane M’Hamdi, Andre Pires da Cunha, and Howard L. Weiner. "IL-6 Inhibits Upregulation of Membrane-Bound TGF-β 1 on CD4+ T Cells and Blocking IL-6 Enhances Oral Tolerance." Journal of Immunology 198, no. 3 (December 30, 2016): 1202–9. http://dx.doi.org/10.4049/jimmunol.1600921.
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Yang, Zhi-Zhang, Deanna M. Grote, Steven C. Ziesmer, Bing Xiu, Nicole R. Yates, Frank J. Secreto, Lucy S. Hodge, Thomas E. Witzig, Anne J. Novak, and Stephen M. Ansell. "Soluble and Membrane-Bound TGF-β-Mediated Regulation of Intratumoral T Cell Differentiation and Function in B-Cell Non-Hodgkin Lymphoma." PLoS ONE 8, no. 3 (March 15, 2013): e59456. http://dx.doi.org/10.1371/journal.pone.0059456.
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Villar, Ana V., Raquel García, Miguel Llano, Manuel Cobo, David Merino, Aquilino Lantero, Mónica Tramullas, Juan M. Hurlé, María A. Hurlé, and J. Francisco Nistal. "BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-β signaling." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1832, no. 2 (February 2013): 323–35. http://dx.doi.org/10.1016/j.bbadis.2012.11.007.
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Hejenkowska, Ewelina D., Hayrettin Yavuz, and Agnieszka Swiatecka-Urban. "Beyond Borders of the Cell: How Extracellular Vesicles Shape COVID-19 for People with Cystic Fibrosis." International Journal of Molecular Sciences 25, no. 7 (March 27, 2024): 3713. http://dx.doi.org/10.3390/ijms25073713.
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The interaction between extracellular vesicles (EVs) and SARS-CoV-2, the virus causing COVID-19, especially in people with cystic fibrosis (PwCF) is insufficiently studied. EVs are small membrane-bound particles involved in cell–cell communications in different physiological and pathological conditions, including inflammation and infection. The CF airway cells release EVs that differ from those released by healthy cells and may play an intriguing role in regulating the inflammatory response to SARS-CoV-2. On the one hand, EVs may activate neutrophils and exacerbate inflammation. On the other hand, EVs may block IL-6, a pro-inflammatory cytokine associated with severe COVID-19, and protect PwCF from adverse outcomes. EVs are regulated by TGF-β signaling, essential in different disease states, including COVID-19. Here, we review the knowledge, identify the gaps in understanding, and suggest future research directions to elucidate the role of EVs in PwCF during COVID-19.
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Mesnard, Daniel, and Daniel B. Constam. "Imaging proprotein convertase activities and their regulation in the implanting mouse blastocyst." Journal of Cell Biology 191, no. 1 (September 27, 2010): 129–39. http://dx.doi.org/10.1083/jcb.201005026.
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Axis formation and allocation of pluripotent progenitor cells to the germ layers are governed by the TGF-β–related Nodal precursor and its secreted proprotein convertases (PCs) Furin and Pace4. However, when and where Furin and Pace4 first become active have not been determined. To study the distribution of PCs, we developed a novel cell surface–targeted fluorescent biosensor (cell surface–linked indicator of proteolysis [CLIP]). Live imaging of CLIP in wild-type and Furin- and Pace4-deficient embryonic stem cells and embryos revealed that Furin and Pace4 are already active at the blastocyst stage in the inner cell mass and can cleave membrane-bound substrate both cell autonomously and nonautonomously. CLIP was also cleaved in the epiblast of implanted embryos, in part by a novel activity in the uterus that is independent of zygotic Furin and Pace4, suggesting a role for maternal PCs during embryonic development. The unprecedented sensitivity and spatial resolution of CLIP opens exciting new possibilities to elucidate PC functions in vivo.