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1
Yang, Liyun, Yan Chen, Sainan Zhu, Dingfang Bu, Lixiang Wang, Xiaojie Jiao, Xuechun Lu, Hongxing Liu, and Ping Zhu. "Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation Using the Donors with the HLA-B*5801-TNFα -308A Haplotype Produced Higher Frequency of Untoward Effects in Acute Lymphocytic Leukemia Patients." Blood 120, no. 21 (November 16, 2012): 2002. http://dx.doi.org/10.1182/blood.v120.21.2002.2002.
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Abstract Abstract 2002 In this study, we investigated the clinical characteristics of acute lymphoblastic leukemia (ALL) patients using sibling donors with HLA-B*5801-TNFα-308A haplotype (B5801-TNF2) for haploidentical or identical hematopoietic stem cell transplantation (HSCT). A total of 136 B-ALL cases and 29 T/NK-ALL cases were recruited. DNA samples from the patients and their siblings were assayed for genotyping of HLA and TNFα at -308 (rs1800629). B5801-TNF2 haplotype in donors was determined by analyzing TNFα -308 and HLA-B genotypes in patients and their family members. Outcomes within 2 years including overall mortality and non-relapse mortality, disease course and complications within 100 days were compared among patients using related donors with HLA-B*5801-TNFα-308A haplotype for haploidentical HSCT (B5801-TNF2+HID group), those using related donor without HLA-B*5801-TNFα-308A haplotype for haploidentical HSCT (B5801-TNF2-HID group), and those using related sibling either B5801-TNF2+ or B5801-TNF2- haplotype for identical HSCT (SID group). In the 165 sibling donors after HSCT, 35 were found to carry HLA-B*5801-TNFα-308A haplotype. There were 21 cases in B5801-TNF2+HID group, 100 cases in B5801-TNF2-HID group, and 44 cases in SID group. Compared patients in B5801-TNF2-HID and SID groups, patients in B5801-TNF2+HID group had higher overall mortality (adjusted P=0.039) and non-relapse mortality within 2 years (adjusted P=0.001), delayed platelet engraftment (adjusted P<0.0001), higher incidences of severe acute graft-versus-host disease (P=0.007), severe late onset hemorrhagic cystitis (P=0.002), blood stream infection (P=0.017), and invasive fungal disease (P=0.004) within 100 days. Therefore, sibling donors carrying HLA-B*5801-TNFα-308A haplotype for haploidentical HSCT caused higher mortality rate and higher frequency of severe complications in ALL recipients. Keywords: HLA-B*5801-TNFα-308A haplotype; acute lymphoblastic leukemia; allogeneic haploidentical hematopoietic stem cell transplantation; allogeneic identical hematopoietic stem cell transplantation Disclosures: No relevant conflicts of interest to declare.
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Ma, Li, Haiyan Gong, Haiyan Zhu, Pei Su, Shannan Cao, Peng Liu, Jianfeng Yao, et al. "Identification Of a Novel Small-Molecule TNFα Inhibitor With Activity Against Inflammation In a Hepatitis Mouse Model." Blood 122, no. 21 (November 15, 2013): 4229. http://dx.doi.org/10.1182/blood.v122.21.4229.4229.
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Abstract Over-expression of tumor necrosis factor α (TNFα) is a hallmark of many inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and septic shock and hepatitis, making it a potential therapeutic target for clinical interventions. To date, significant advances have been made in the development of biological agents targeting TNFα and its signaling components. There are several well known commercial TNFα inhibitors, such as infliximab, adalimumab and etanercept, all of which are TNFα antibodies or TNFR1-Fc chimeras and function to prevent TNFα from binding to its receptor. Those biomacromolecular agents have been proved to be effective in the treatment of inflammatory bowel disease and rheumatoid arthritis due to their unique superiorities such as high specificity. However, several severe limitations such as poor stability, cost-ineffective commercial-scale production and exclusion from blood/brain barrier have also emerged. Instead, small-molecule chemical compounds have been appreciated as appropriate alternatives for overcoming most disadvantages associated with macromolecular inhibitors. Furthermore, they offer additional clinical benefits such as simpler preparation for oral medicine. Now by the use of computer-aided drug design (CADD) and cell-based assays in vitro, several selective small-molecule antagonists of TNFα activity have been identified. They include broad-spectrum inhibitors targeting the key molecules of the intracellular TNFα pathway, functionally uncharacterized inhibitors of TNFα expression, inhibitors of the processing enzyme TNFα converting enzyme (TACE), and molecules that directly bind to TNFR or prevent TNFα-TNFR interactions. Although the small-molecule inhibitors are capable of blocking the biological activity of TNFα in vitro, few have been shown to abrogate or reduce TNFα-induced inflammatory responses in vivo and exhibit high IC50 and severe side effects. Also, none of the small-molecular inhibitors have been reported to successfully block TNFα’s interaction with TNFR through direct binding to TNFα. Thus, development of small molecules for TNFα therapy remains a major challenge. In this study, to explore chemical inhibitors against TNFα activity, we applied CADD combined with in vitro and cell-based assays and identified a lead chemical compound (named as C87 thereafter) from a compound library including about 90,000 small molecular compounds, which directly binds to TNFα indicated by SPR assay, and it potently inhibits TNFα-induced cytotoxicity (IC50=8.73μM) and effectively blocks TNFα–triggered signaling activities. More importantly, by using a murine acute hepatitis model, we showed that C87 attenuates TNFα-induced inflammation, thereby markedly reducing injuries to the liver and improving animal survival. Thus, our results lead to a novel and highly specific small-molecule TNFα inhibitor, which can be potentially used to treat TNFα mediated inflammatory diseases. Disclosures: No relevant conflicts of interest to declare.
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Gharamti, Amal, Omar Samara, Anthony Monzon, Lilian Vargas Barahona, Sias Scherger, Kristen DeSanto, Daniel B. Chastain, et al. "1003. Cytokine Levels in Sepsis and TNFα Association with Mortality but not Sepsis Severity or Infection Source: a Systematic Review and Meta-analysis." Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S592. http://dx.doi.org/10.1093/ofid/ofab466.1197.
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Abstract Background Sepsis is a global health problem associated with significant morbidity and mortality and is attributed to a “cytokine storm.”. However, anti-cytokine therapies have failed to lower sepsis mortality in clinical trials. Linking cytokine excess to sepsis pathogenesis requires quantification of cytokine levels in sepsis. This systematic review and meta-analysis characterizes levels of key cytokines in the circulation of sepsis patients and relates TNFα levels to mortality and patient characteristics. Methods Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched from 1946 to May 2020 for studies in English disclosing cytokine levels in sepsis. Keywords included sepsis, septic shock, purpura fulminans, and tumor necrosis factor (TNF)α. We related cytokine amounts to 28-day mortality. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). This systematic review is registered in PROSPERO under number CRD42020179800. Results A total of 3656 records were identified. After exclusions, 103 studies were included. Among these studies, 72 disclosed TNFα levels, 25 showed interleukin (IL)-1β levels, and 6 presented interferon (IFN)γ levels. The pooled estimate mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% CI, 39.8-85.8 pg.ml; I2 = 99.4%). Pooled estimate means for IL-1α and IFNγ in sepsis patients were 21.8 pg/ml (95% CI, 12.6-37.8 pg.ml; I2 =99.8%) and 63.3 pg/ml (95% CI, 19.4-206.6 pg/ml; I2 = 99.7%), respectively. Elevated TNFα concentrations were associated with increased 28-day mortality (P=0.001). In a subgroup analysis, TNFα levels did not relate to sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score (figure 1). In a metaregression, TNFα associated with age, percentage of females and mortality at 28 days. Figure 1: A: TNFa levels according to sepsis source. B: TNFa levels according to measurement technique. C: TNFa levels according to presence or absence of cardiovascular disease. D: TNFa levels according to presence or absence of malignancy. E: TNFa levels according to sepsis severity. F: TNFa levels in fungal compared to other causes of sepsis (Yes=fungal sepsis; No= Other types of sepsis). G: TNFa levels according to SOFA score. H: TNFa levels and mortality at 28 days. Conclusion We presented levels of TNFα, IL-1β, and IFNγ in human sepsis and showed that TNFα elevations are associated with sepsis mortality. TNFα concentrations did not correlate with sepsis severity. We believe the concept that elevated cytokines cause sepsis should be revisited in the context of these data. Disclosures All Authors: No reported disclosures
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Bertolaccini, M. L., J. S. Lanchbury, A. R. Caliz, K. Katsumata, R. W. Vaughan, E. Kondeatis, M. A. Khamashta, T. Koike, G. R. V. Hughes, and T. Atsumi. "Plasma Tumor Necrosis Factor α Levels and the –238* A Promoter Polymorphism in Patients with Antiphospholipid Syndrome." Thrombosis and Haemostasis 85, no. 02 (2001): 198–203. http://dx.doi.org/10.1055/s-0037-1615676.
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Summary Objectives. To explore the possible involvement of the proinflammatory and prothrombotic cytokine TNFα in APS by determining the plasma levels in patients and to test for association of TNFA promoter polymorphisms and HLA class II genotypes with both plasma TNF and disease. Patients and Method. We studied 83 Caucasoid patients with APS and two groups of healthy controls. TNFα levels were determined in plasma from 35 patients’ and 21 controls using a highly sensitive sandwich ELISA. The full patient group was genotyped together with 95 ethnically matched healthy controls. -308 and -238 TNFA promoter polymorphisms were assessed by ARMS-PCR. HLA-DQB1, DQA1 and DRB1 genotypes were determined by PCR using sequence specific primers. Results. TNFα levels were significantly higher in patients with APS than healthy controls (median 2.95 pg/ml [range 0.51-10.75] vs. 0.95 pg/ml [0.51-1.6], respectively; p = 0.0001). Frequencies of TNFA-308*2 genotype did not differ between patients and controls. In contrast, TNFA-238*A positive genotype was more frequent in APS patients with arterial thrombosis and pregnancy loss than in controls (OR 3.7 [95% CI 1.37-10.1], p = 0.007 and OR 3.95 [95% CI 1.3-11.7], p = 0.01; respectively). DQB1*0303-DRB1*0701 haplotype was associated with TNFA-238*A in the control group (OR 96.0 [95% CI 9.6-959], p 0.0001) as well as in APS patient’s group (OR 54.2 [95% CI 9.6-306.5], p 0.0001). Conclusions. Raised plasma TNFα levels were found in patients with APS. As a prothrombotic and proinflammatory cytokine, TNFα may be involved in the development of clinical features of APS. The lack of correlation between the TNFA-238 polymorphism and plasma levels associated with disease suggests that the TNFα genetic marker may only indirectly relate to protein levels by virtue of allelic association with a functional marker which may reside in the HLA class II region.
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Tani-Ishii, N., A. Tsunoda, T. Teranaka, and T. Umemoto. "Autocrine Regulation of Osteoclast Formation and Bone Resorption by IL-1α and TNFα." Journal of Dental Research 78, no. 10 (October 1999): 1617–23. http://dx.doi.org/10.1177/00220345990780100601.
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Bone resorption is regulated by the cytokines within marrow cells that mediate osteoclast formation and activation. IL-1 and TNF induce bone resorption by stimulating the production of osteoclast-like multinucleated cells and by increasing the bone-resorbing activity of formed osteoclasts. This study was designed to detect IL-1 and TNF in osteoclasts in vitro and to determine whether these cytokines up-regulate osteoclast differentiation and bone resorption. The production of IL-1α, -β, and TNFa, β in osteoclasts was examined immunohistochemically and by in situ hybridization. In the co-culture of C57BL/6N mouse bone marrow and MC3T3-G2/PA6 cells, a colony of osteoclasts formed, and IL-1α and TNFa were detected. However, IL-1β and TNF β were not detected. To investigate the role of IL-1α and TNFα from osteoclasts, we enumerated TRAP-positive cells and measured the resorption pit areas in the presence of antibodies against IL-1α and TNFα. The addition of antibodies against IL-1α and TNFα to the co-culture system decreased the number of TRAP-positive colonies at seven days after incubation (anti-IL-1α, 25.0 ± 2.3%; anti-TNFα, 41.7 ± 3.7%; anti-IL-1α + anti-TNFα, 40.5 ± 1.3%; and control, 100%), and the ratio of mononuclear to multinuclear cells had changed (anti-IL-1α, 90:10; anti-TNFα, 75:25; anti-IL-1α+ anti-TNFα, 88:12; and control, 60:40). The total pit areas per dentin slice also decreased with the addition of antibodies (anti-IL-1α, 28,828; anti-TNFα, 49,249; anti-IL-1α + anti-TNFα, 30,685; and control, 303,139 mm2). These results suggest that local production of IL-la and TNFα by osteoclasts is an important mechanism for regulating the osteoclast differentiation and bone resorptive process.
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Rosenzweig, Holly L., Manabu Minami, Nikola S. Lessov, Sarah C. Coste, Susan L. Stevens, David C. Henshall, Robert Meller, Roger P. Simon, and Mary P. Stenzel-Poore. "Endotoxin Preconditioning Protects against the Cytotoxic Effects of TNFα after Stroke: A Novel Role for TNFα in LPS-Ischemic Tolerance." Journal of Cerebral Blood Flow & Metabolism 27, no. 10 (February 28, 2007): 1663–74. http://dx.doi.org/10.1038/sj.jcbfm.9600464.
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Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-α (TNFα) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFα in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFα are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFα before middle cerebral artery occlusion in mice and show that TNFα is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFα are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFα (~ threefold) and the proximal TNFα signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (~ 2.5-fold), which may neutralize the effect of TNFα and reduce TNFα-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFα after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFα in the setting of ischemia. Our studies suggest that TNFα is a twin-edged sword in the setting of stroke: TNFα upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFα signaling during ischemia confers neuroprotection after LPS preconditioning.
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Droessler, Linda, Valeria Cornelius, Alexander G. Markov, and Salah Amasheh. "Tumor Necrosis Factor Alpha Effects on the Porcine Intestinal Epithelial Barrier Include Enhanced Expression of TNF Receptor 1." International Journal of Molecular Sciences 22, no. 16 (August 14, 2021): 8746. http://dx.doi.org/10.3390/ijms22168746.
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Tumor necrosis factor alpha (TNFα) has been shown to impair the intestinal barrier, inducing and maintaining inflammatory states of the intestine. The aim of the current study was to analyze functional, molecular and regulatory effects of TNFα in a newly established non-transformed jejunal enterocyte model, namely IPEC-J2 monolayers. Incubation with 1000 U/mL TNFα induced a marked decrease in transepithelial electrical resistance (TEER), and an increase in permeability for the paracellular flux marker [3H]-D-mannitol compared to controls. Immunoblots revealed a significant decrease in tight junction (TJ) proteins occludin, claudin-1 and claudin-3. Moreover, a dose-dependent increase in the TNF receptor (TNFR)-1 was detected, explaining the exponential nature of pro-inflammatory effects, while TNFR-2 remained unchanged. Recovery experiments revealed reversible effects after the removal of the cytokine, excluding apoptosis as a reason for the observed changes. Furthermore, TNFα signaling could be inhibited by the specific myosin light chain kinase (MLCK) blocker ML-7. Results of confocal laser scanning immunofluorescence microscopy were in accordance with all quantitative changes. This study explains the self-enhancing effects of TNFα mediated by MLCK, leading to a differential regulation of TJ proteins resulting in barrier impairment in the intestinal epithelium.
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Li, Yusheng, Darrell L. Dinwiddie, Kevin S. Harrod, Yong Jiang, and K. Chul Kim. "Anti-inflammatory effect of MUC1 during respiratory syncytial virus infection of lung epithelial cells in vitro." American Journal of Physiology-Lung Cellular and Molecular Physiology 298, no. 4 (April 2010): L558—L563. http://dx.doi.org/10.1152/ajplung.00225.2009.
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MUC1 is a transmembrane glycoprotein expressed on the apical surface of airway epithelial cells and plays an anti-inflammatory role during airway bacterial infection. In this study, we determined whether the anti-inflammatory effect of MUC1 is also operative during the respiratory syncytial virus (RSV) infection. The lung epithelial cell line A549 was treated with RSV, and the production of TNFα and the levels of MUC1 protein were monitored temporally during the course of infection by ELISA and Western blot analysis. Small inhibitory RNA (siRNA) transfection was utilized to assess the role of MUC1 in regulating RSV-mediated inflammatory responses by lung epithelial cells. Our results revealed that: 1) following RSV infection, an increase in MUC1 level was preceded by an increase in TNFα production and completely inhibited by soluble TNF receptor (TNFR); and 2) knockdown of MUC1 using MUC1 siRNA resulted in a greater increase in TNFα level following RSV infection compared with control siRNA treatment. We conclude that the RSV-induced increase in the TNFα levels upregulates MUC1 through its interaction with TNFR, which in turn suppresses further increase in TNFα by RSV, thus forming a negative feedback loop in the control of RSV-induced inflammation. This is the first demonstration showing that MUC1 can suppress the virus-induced inflammatory responses.
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Kapás, L., A. B. Cady, M. R. Opp, A. E. Postlethwaite, J. M. Seyer, and J. M. Krueger. "Somnogenic and pyrogenic activity of TNFα, TNFβ and fragments of TNFα." International Journal of Immunopharmacology 13, no. 6 (January 1991): 717. http://dx.doi.org/10.1016/0192-0561(91)90210-x.
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Sanz, Maria-Jesus, Adele Hartnell, Patricia Chisholm, Cindy Williams, Dawn Davies, Vivian B. Weg, Marc Feldmann, Mark A. Bolanowski, Roy R. Lobb, and Sussan Nourshargh. "Tumor Necrosis Factor α-Induced Eosinophil Accumulation in Rat Skin Is Dependent on α4 Integrin/Vascular Cell Adhesion Molecule-1 Adhesion Pathways." Blood 90, no. 10 (November 15, 1997): 4144–52. http://dx.doi.org/10.1182/blood.v90.10.4144.
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Abstract Tumor necrosis factor α (TNFα) is a cytokine implicated in the pathogenesis of numerous chronic and acute inflammatory conditions. In the present study, we have characterized the ability of TNFα in inducing eosinophil accumulation in rat skin and have shown the inhibitory effects of anti-α4 integrin and anti–vascular cell adhesion molecule-1 (VCAM-1) antibodies on this response. The intradermal injection of recombinant human TNFα induced a slowly developing, dose-dependent accumulation of 111In-eosinophils in rat skin that was maximal at the dose of 10−11 mol/site. Coadministration of TNFα with the soluble TNFα receptor (p55)-IgG fusion protein (TNFR-IgG) totally inhibited the 111In-eosinophil accumulation induced by the cytokine. The TNFα-induced 111In-eosinophil accumulation was not affected after pretreatment of rats with the platelet-activating factor (PAF) receptor antagonist UK-74,505 or the antihuman interleukin-8 monoclonal antibody (MoAb) DM/C7. In contrast, the intravenous administration of an anti-α4 integrin MoAb, HP2/1 (3.5 mg/kg), or an anti–VCAM-1 MoAb, 5F10 (2 mg/kg), greatly inhibited the 111In-eosinophil accumulation induced by TNFα (the responses detected at 10−11 mol/site were inhibited by 78% and 50%, respectively). These results show that TNFα is an effective inducer of eosinophil accumulation in vivo, with this response being dependent on an interaction between α4 integrins and VCAM-1.
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Juncadella, Ignacio, Chao-ting Wang, Gary Caviness, and Gerald Nabozny. "A pivotal interplay between TNF alpha and the IL-23-axis cytokines in regulating primary human intestinal epithelial cell apoptosis (MUC5P.753)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 138.11. http://dx.doi.org/10.4049/jimmunol.194.supp.138.11.
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Abstract TNFα induces intestinal epithelial cell (IEC) cell death, likely responsible for barrier dysfunction and mucosal damage. However, studies addressing the role of TNFα on epithelial damage rely on Caco2 or HT29 cell lines and rarely primary IECs. Interleukin-23 (IL-23) pathway is genetically associated to IBD pathogenesis. IL-23-responsive cells produce the signature cytokines, interleukin-17 (IL-17) and interleukin-22 (IL-22). These cytokines are elevated in IBD patients, and may contribute to disease pathology. Here, we describe the synergistic interplay between TNFα and the IL-23 axis on IEC apoptosis. Using human IECs and organotypic cultures, we demonstrate that; TNFα treatment induces moderate to low proinflammatory gene expression compared to IL-17 and IL-22, TNFα and IL22 stimulation leads to upregulation of proinflammatory and proapoptotic genes and, IL22 but not IL17 enhances TNFα-induced cell death. Interestingly, the effect of IL22 was independent of IFNγ, contrary to previous findings. IL-22 stimulation resulted in TNFRI and TNFRII expression, likely making the epithelium more responsive to TNFα-induced cell death. In conclusion, this is the first demonstration between TNFa and the IL23-axis in driving IEC apoptosis and cell death. Also, while TNFα and the IL-23 axis contribute to IBD pathogenesis via different approaches; the interplay of these pathways may be linked to promote epithelial cell damage and barrier dysfunction resulting in disease progression.
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Yu, Nanmeng, and George J. Weiner. "Abstract 5596: TNFα production by myeloid DCs in response to rituximab induces monocyte and NK cell proliferation and survival." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5596. http://dx.doi.org/10.1158/1538-7445.am2022-5596.
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Abstract Background: Rituximab is a central component of chemoimmunotherapy for B cell lymphomas. With over two decades in clinical use, new insights into its mechanisms of action continue to emerge. Rituximab infusion into patients results in elevated levels of TNFα in patient sera. However, our understanding of the mechanism of TNFα production in the context of rituximab and its role in anti-tumor immunity remain limited. In our study, we sought to determine the major producers of TNFα following rituximab treatment and the effect of rituximab-induced TNFα on anti-tumor effector cells. Methods: Peripheral blood mononuclear cells (PBMCs) from normal donors were cocultured in vitro with CD20-expressing Raji cells for 1 to 7 days. The coculture was treated with rituximab or non-specific antibody trastuzumab. Recombinant TNFα or TNFα blocking antibody infliximab were used to test the effect of TNFα in the rituximab- or trastuzumab-treated coculture system. ELISA was used to evaluate TNFα production in culture supernatant. Multicolor flow cytometry was used to evaluate for phenotypic and functional changes with TNFα treatment or blockade in various immune cell populations. Results: TNFα was robustly produced by PBMCs when treated with rituximab. This production was mediated by the Fc portion of rituximab antibody, as rituximab Fab elicited very little if any TNFα response from PBMCs. Myeloid dendritic cells (HLA-DR+CD123-CD11c+) were the key producers of TNFα in response to rituximab. In the absence of antibody therapy, recombinant TNFα treatment induced proliferation and survival of two major effector cells in the peripheral blood: monocytes and NK cells as determined by cell count and percent of Ki67+ cells. TNFα blockade using infliximab inhibited monocyte and NK cell proliferation and survival. TNFα blockade also protected Raji cells from rituximab-mediated killing. Conclusions: Rituximab-induced TNFα production promotes the proliferation and survival of monocytes and NK cells. Myeloid dendritic cells are necessary for TNFα production in this context. These results highlight the complexity of the immune response to rituximab treatment. Additional studies are ongoing exploring the role TNFa plays in the therapeutic response to rituximab. Citation Format: Nanmeng Yu, George J. Weiner. TNFα production by myeloid DCs in response to rituximab induces monocyte and NK cell proliferation and survival [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 5596.
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Schürks, Markus, Pamela M. Rist, Robert YL Zee, Daniel I. Chasman, and Tobias Kurth. "Tumour necrosis factor gene polymorphisms and migraine: A systematic review and meta-analysis." Cephalalgia 31, no. 13 (October 2011): 1381–404. http://dx.doi.org/10.1177/0333102411419022.
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Background: Data on the association between TNFα and TNFβ gene polymorphisms and migraine are conflicting. Methods: We performed a systematic review and meta-analysis of studies published until January 2011. We used data from published papers and as provided after contact with the authors. We calculated study specific odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models as well as pooled effect estimates. Results: Among the ten studies identified, the best evidence is available for the TNFα −308G>A and TNFβ 252A > G polymorphisms indicating no overall association with migraine. Subgroup analyses suggested that the A allele of the TNFα −308G > A variant more than doubles the risk for migraine among populations with a heterogeneous ethnic background, which was driven by associations for migraine without aura (additive model: pooled OR = 2.87, 95% CI 1.86–4.43). Further, the risk for migraine with aura was increased among Asian populations (additive model: pooled OR = 1.71, 95% CI 1.07–2.71). Both observed effects were stronger among females than males. Conclusions: Our results indicate no overall association between TNFα and TNFβ gene variants and migraine. However, associations differed among specific populations. Our findings need to be treated with caution and further targeted research is warranted to evaluate population-specific effects including population stratification.
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Choi, Hyehun, Ryan J. Stark, Benjamin S. Raja, Anna Dikalova, and Fred S. Lamb. "Apoptosis signal-regulating kinase 1 activation by Nox1-derived oxidants is required for TNFα receptor endocytosis." American Journal of Physiology-Heart and Circulatory Physiology 316, no. 6 (June 1, 2019): H1528—H1537. http://dx.doi.org/10.1152/ajpheart.00741.2018.
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Tumor necrosis factor-α (TNFα) is a proinflammatory cytokine that is closely linked to the development of cardiovascular disease. TNFα activates NADPH oxidase 1 (Nox1) and reactive oxygen species (ROS), including superoxide (O2·−), production extracellularly is required for subsequent signaling in vascular smooth muscle cells (VSMCs). Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that is activated by oxidation of associated thioredoxin. The role of ASK1 in Nox1-mediated signaling by TNFα is poorly defined. We hypothesized that ASK1 is required for TNFα receptor endocytosis and subsequent inflammatory TNFα signaling. We employed a knockdown strategy to explore the role of ASK1 in TNFα signaling in VSMCs. siRNA targeting ASK1 had no effect on TNFα-induced extracellular O2·− production. However, siASK1 inhibited receptor endocytosis as well as phosphorylation of two endocytosis-related proteins, dynamin1 and caveolin1. Intracellular O2·− production was subsequently reduced, as were other inflammatory signaling steps including NF-κB activation, IL-6 production, inducible nitric oxide synthase and VCAM expression, and VSMC proliferation. Prolonged exposure to TNFα (24 h) increased tumor necrosis factor receptor (TNFR) subtype 1 and 2 expression, and these effects were also attenuated by siASK1. ASK1 coimmunoprecipitated with both Nox1 and the leucine rich repeat containing 8A anion channel, two essential components of the TNFR1 signaling complex. Activation of ASK1 by autophosphorylation at Thr845 occurs following thioredoxin dissociation, and this requires the presence of Nox1. Thus, Nox1 is part of the multiprotein ASK1 signaling complex. In response to TNFα, ASK1 is activated by Nox1-derived oxidants, and this plays a critical role in translating these ROS into a physiologic response in VSMCs. NEW & NOTEWORTHY Apoptosis signal-regulating kinase 1 (ASK1) drives dynamin1 and caveolin1 phosphorylation and TNFα receptor endocytosis. ASK1 modulates TNFα-induced NF-κB activation, survival, and proliferation. ASK1 and NADPH oxidase 1 (Nox1) physically associate in a multiprotein signaling complex. Nox1 is required for TNFα-induced ASK1 activation.
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Tian, Tian, Krista Dubin, Qiushuang Jin, Ali Qureshi, Sandra King, Luzheng Liu, Xiaodong Jiang, George Murphy, Thomas Kupper, and Robert Fuhlbrigge. "Interruption with TNFα/TNFR1 function impairs host immune response against cutaneous vaccinia virus infection (52.8)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 52.8. http://dx.doi.org/10.4049/jimmunol.188.supp.52.8.
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Abstract One strategy adopted by vaccinia virus (VV) to evade the host immune system is to encode homologs of TNF receptors (TNFR) that block TNFα function. The response to VV skin infection under conditions of TNFα deficiency, however, has not been reported. We found that TNFR1-/- developed larger skin lesions with higher virus levels after VV scarification. Following their recovery, these TNFR1-/- mice were fully protected against lethal VV intranasal challenge, suggesting their effective memory immune response. A functional systemic immune response of TNFR1-/- mice was further demonstrated by enhanced production of VV-specific IFNγ and CD8+ T cells in spleens and draining lymph nodes as well as efficient T cell skin homing. Interestingly, bone marrow (BM) reconstitution studies using WT BM →TNFR1-/- mice, but not TNFR1-/- BM → WT mice, reproduced the original results seen in TNFR1-/- mice, indicating that TNFR1 deficiency in resident skin cells, rather than hematopoietic cells, accounts for the impaired cutaneous immune response. Similar phenotype was also found in in TNFα-/- mice following VV scarification while both WT BM→ TNFα-/- mice and TNFα-/-BM →WT mice developed significantly larger skin lesions with higher virus counts than the control chimeric mice.Therefore, while the target of TNFα action is restricted to skin stromal components, the source of TNFα produced in response to VV infection would appear to include both hematopoietic cells and radioresistant skin elements.
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Dhar, A., A. Wilson, V. Reid, T. Clark, C. Tibbatts, A. Dallongeville, J. Robertson, J. Eaton, H. Cranmer, and G. Owen. "P633 Choice of first biologic in moderate to severe ulcerative colitis – a decision analysis using time-on-treatment and UK costs." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i765—i766. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0763.
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Abstract Background Vedolizumab and anti-TNFα drugs are biologics that are used to treat moderate to severe ulcerative colitis (UC). In the UK, the decision of which drug to use at first-line is often based on a combination of clinical factors and the price of the drug (based on the one-year cost analysis from the NICE appraisal). The cost of the treatment pathway is rarely considered. Therefore, we investigated whether the choice of first-line biologic affects time-on-treatment and the overall treatment pathway costs by creating a cost model for vedolizumab followed by an anti-TNFα (VDZ–anti-TNFα) compared to anti-TNFα followed by vedolizumab (anti-TNFα–VDZ). Methods A targeted literature search identified 19 studies reporting time-on-treatment data for vedolizumab or anti-TNFαs in UC. We pooled data into four categories: 1) vedolizumab in people who were biologic-naïve (VDZ-1L), 2) anti-TNFα in people who were biologic-naïve (anti-TNFα-1L), 3) vedolizumab after first-line anti-TNFα (VDZ-2L) and 4) anti-TNFα after first-line vedolizumab (anti-TNFα-2L). We then fitted parametric curves to inform time-on-treatment estimates for each category. We calculated ‘direct’ treatment costs by considering drug acquisition, drug administration, dose escalation, concomitant use of immunomodulators and drug monitoring; all costs were sourced from four NHS hospital trusts (cost year 2022). As the duration of the anti-TNFα–VDZ pathway was shorter in duration than VDZ–anti-TNFα (62- vs 44-months), we modelled third line options in the shorter pathway using a weighted basket approach. Third line options included colectomy, tofacitinib, ustekinumab or dose escalation of second-line biologic. Results Over the 62-month time horizon (duration of the longer VDZ–anti-TNFα pathway), pathway costs per patient were similar: £41,439 for VDZ–anti-TNFα and £48,027 for anti-TNFα–VDZ (or £8,021 per year and £9,295 per year, respectively). The model predicted that using vedolizumab first-line delayed the time to costly third-line therapies compared to first-line anti-TNFα. This delay resulted from the pooled time-on-treatment data: VDZ-1L median time-on-treatment 43-months (n=585 people) and anti-TNFα-2L 19-months (n=47); anti-TNFα-1L 17-months (n=7690) and VDZ-2L 27-months (n=549). Conclusion When viewed over a longer period and considering all associated direct costs, a biologic treatment pathway that begins with first-line vedolizumab is not more expensive than one beginning with first-line anti-TNFα in treating moderate to severe UC in the UK. The model shows that considering the longer-term costs of a treatment pathway can give a different result compared to considering the short-term costs of single therapies alone.
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Qasem, Ahmad, and Saleh Naser. "Role of TNFα Antagonists in Susceptibility to Mycobacterial Infection in Association with Genetic Polymorphisms in Crohn’s Disease." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 45.14. http://dx.doi.org/10.4049/jimmunol.200.supp.45.14.
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Abstract Crohn’s disease (CD) is a relapsing inflammatory bowel disease that has been associated with bacterial triggers such as Mycobacterium avium subspecies paratuberculosis (MAP). Overreactive immune response in CD patients involves a significant elevation in Tumor Necrosis Factor alpha (TNFα), which causes upregulation in multiple cytokine levels, leading to formation and maintenance of granuloma. Standard CD treatment includes immunomodulators and biologics such as Anti-TNFα. We hypothesize that blocking TNFα promotes MAP survival which worsens the disease condition. Therefore, CD treatment plan should include MAP-specific antibiotics and novel cytokine targets based on personalized medicinal approach. RHB-104, a triple antibiotics formulation ((63.3 %) clarithromycin, (6.7 %) clofazimine, and (30 %) rifabutin), recombinant TNFα, adalimumab (Humira®), and certolizumab pegol (Cimzia®) were evaluated in vitro for effect on MAP culture and macrophages infected with MAP. As expected, RHB-104 was detrmintal to MAP (MIC< 2ug/mL), while anti-TNFα therapeutics had no direct bactericidal effects at concentrations as high as 4x Cmax. Recombinant TNFα reduced MAP survival in infected macrophages by 2.63 logs. On the contrary, both anti-TNFα therapeutics promoted MAP survival by 1.54 logs. Additionally, we have identified 2 significant single nucleotide polymorphisms (rs767455 and rs3397) related to TNFR superfamily 1(A/B) in 54 CD patients compared to 50 healthy subjects by using TaqManTM genotyping assay. This study should provide i) data about the safety of Anti-TNFα biologics in CD patients-associated with MAP infection and ii) predictions toward response to treatment plan based on patient’s pharmacogenomics.
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Sandberg-Wollheim, M., E. Ciusani, A. Salmaggi, and F. Pociot. "An evaluation of tumor necrosis factor microsatellite alleles in genetic susceptibility to multiple sclerosis." Multiple Sclerosis Journal 1, no. 3 (November 1995): 181–85. http://dx.doi.org/10.1177/135245859500100309.
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We have analyzed the distribution of tumor necrosis factor (TNF) a and-b microsatellite alleles in HLA-DQ and-DR typed Swedish patients with multiple sclerosis (MS) (n=l22) and ethnically matched control subjects (n=l78). We found significant differences in the frequencies of TNFa and TNFb alleles between patients and controls. TNFal I was significantly associated with MS. This was also the case for the combination of TNFal I with TNFb4. However, TNFal I (alone or in combination with TNFb4) did not show any disease association independent of DQA 1*01021 DQBI*0602/DR2, whereas the previously reported strong association with HLA-DQAI*0102/DQBI*0602/DR2 in Scandinavian populations was confirmed. Therefore the association of TNFal I (and TNFb4) is most likely secondary to the increase of DQAI*0102/DQBl*0602/DR2 in MS patients. The proportion of TNFa6 positive individuals was lower among DR2-negative MS patients than among DR2-negative controls (p=0.08). Since the presence of the TNFab allele correlates with low TNFα production in response to lipopolysaccharide, it could be speculated that DR2-negative MS patients have an increased risk of being high TNFα producers in response to exogenous stimuli.
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Kokolakis, Georgios, Robert Sabat, Sabine Krüger-Krasagakis, and Jürgen Eberle. "Ambivalent Effects of Tumor Necrosis Factor Alpha on Apoptosis of Malignant and Normal Human Keratinocytes." Skin Pharmacology and Physiology 34, no. 2 (2021): 94–102. http://dx.doi.org/10.1159/000513725.
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<b><i>Introduction:</i></b> Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that may paradoxically induce either apoptosis or cell survival. It mediates its activity through binding of TNF-receptor (TNFR) 1 or 2. TNFR1 is mainly responsible for transmitting apoptotic signals. The activation of apoptotic mechanisms can either be intrinsic (mitochondrial) or extrinsic (death receptors). Death ligands such as TNF-related apoptosis-inducing ligand (TRAIL) specifically induce extrinsic apoptosis, while cytostatic drugs such as 5-fluorouracil (5FU) induce intrinsic apoptosis. <b><i>Objectives:</i></b> To investigate the effects of TNFα on apoptosis in malignant and normal human keratinocytes. <b><i>Methods:</i></b> Human cutaneous squamous cell carcinoma (SCC) cell line SCC-13 and immortalized human keratinocytes HaCaT as well as primary normal human keratinocytes (PNHK) were stimulated with TNFα and then treated either with TRAIL or 5FU. Cell viability and cell proliferation, DNA fragmentation, apoptosis, and cytotoxicity were determined by WST-1 proliferation assay, ELISA, flow cytometry, and colorimetric analysis of lactate dehydrogenase, respectively. In addition, Western blotting was performed for analysis of caspase-3. <b><i>Results:</i></b> TNFα affected viability of SCC-13 and HaCaT cells in combination with 5FU or TRAIL. In contrast, TNFα did not influence cell viability of PNHK. It enhanced the apoptotic effects of both extrinsic and intrinsic stimuli in SCC-13 and HaCaT. In clear contrast, TNFα protected PNHK against TRAIL- and 5FU-induced apoptosis. The effects were dose-dependent and TNFα-specific; furthermore, the apoptosis pathway was caspase-dependent. <b><i>Conclusions:</i></b> In summary, opposing effects of TNFα in malignant versus normal human keratinocytes were observed with possibly relevant clinical implications, when patients are treated with TNFα inhibitors.
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Li, Bin, Matthew Pagni, Justin Cates, D. Brent Polk, and Pampee P. Young. "TNF-α-Mediated Tumor Promotion Is Characterized by Enhanced Vasculogenesis and Generation of Myeloid/Endothelial Vascular Leukoctyes." Blood 110, no. 11 (November 16, 2007): 3905. http://dx.doi.org/10.1182/blood.v110.11.3905.3905.
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Abstract Whereas in many contexts myeloid cells are cytotoxic, it is well-established that as yet unknown microenvironment cues instruct the infiltrating tumor associated myeloid cells (TAMs) to drive malignant progression and dissemination. Recently, we and others have characterized a significant subpopulation of tumor associated myeloid cells that co-express endothelial and myeloid markers designated “vascular leukocytes”. Studies suggest that vascular leukocytes play an important role in tumor progression and also demonstrate modest contribution to functional vessels, i.e. vasculogenesis, suggesting that they represent a critical tumor-promoting TAM subpopulation. We have identified TNFα as a key regulator of the vascular transdifferentiation of myeloid progenitors in vitro and within the tumor milieu. TNFα at 40ng/ml significantly increased the numbers of flk-1/VE-cadherin dual positive, early outgrowth EPCs from human CD14+ cells by day 7 (about five fold of the control), starting with increased spindle-shaped population appeared as early as day 3. Consistent with this, we observed increased flk-1 expression by ∼9-fold (p<0.05) in cells treated with 40ng/ml TNFα by real time RT-PCR. Transcripts for VE-cadherin and tie2, both endothelial-enriched, were detected by day 3 in cells exposed to 40ng/ml TNFa but not in its absence (control). TNFα-directed upregulation of endothelial markers in mouse monocytes in vitro was dependent on TNFα receptors as monocytes isolated from mice lacking both TNF receptors displayed significantly delayed endothelial marker upregulation. These data suggested that TNF was a component of the molecular pathway that accelerated, but was not required for, endothelial transdifferentiation of murine and human myeloid cells. Enhanced TNFα expression in both B16 murine melanoma and PyV-mT tumor showed local TNFα significantly promoted tumor growth versus control (>5-fold increase for B16 tumor, p=0.04; >8-fold increase for PyV-mT tumor, p<0.01). Both tumor models indicated that overexpressing TNFα caused higher vascular density over control, while tumor necrosis was significantly reduced. Additionally, we observed increased bone marrow-derived vessels (vasculogenesis) in mouse TNFα-overexpressing tumors, which can be specifically inhibited by an anti-TNFα blocking antibody. A significant increase in association of vascular leukoctyes was detected in tumors overexpressing TNFα by FACs, which was abrogated in the mice lacking TNF receptors. Interestingly, TNF-overexpressing tumors did not recruit greater overall numbers of tumor-associated (myeloid or lymphoid) leukocytes, suggesting a specific role in myeloid to endothelial transdifferentiation in vivo. Our studies suggest that TNFα constitutes part of the microenvironment repertoire that biases recruited myeloid cells towards a proangiogenic/provasculogenic phenotype.
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Abbas Egbariya, H., M. Ben-Shoshan, Z. Braun, T. Berger, M. Granot, N. Loberman-Nachum, B. Vais, O. Gal Mor, A. Amir, and Y. Haberman. "P016 Colonoids derived from UC patients retain higher transcriptional response to inflammatory triggers in-vitro, even after several passages." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i144. http://dx.doi.org/10.1093/ecco-jcc/jjab232.145.
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Abstract Background Ulcerative colitis (UC) patients show high variations in disease phenotype and response to therapy. Intestinal epithelia play a key role in UC pathogenesis, and therefore patient-derived epithelial model to study this variation are warranted. Few studies suggest that colonoids derived from UC patients retain some disease-related transcriptional and epigenetic changes, but they also raise questions regarding their persistence in culture. Here, we aimed to characterize if UC epithelial dysfunctions and response to inflammatory signals retained in colonoid culture. Methods Rectal biopsies were used to generate epithelial organoids (colonoids) that were grown through 5–10 passages using L-WRN conditioned medium. Media and total RNA were collected for measuring CXCL1 secretion using ELISA and qPCR, respectively. Results 3 control and 5 UC patients-derived colonoids were generated. Median age was 17 years and 75% were females. Control patients were evaluated for loose stool, abdominal pain, and anemia, but had normal rectal mucosa endoscopically and histologically. UC included newly diagnosed and established patients. Colonoids were allowed to differentiate for 48 hours before applying different inflammatory cocktails to induce inflammation for 24 h with IFNγ+LPS, IFNγ+TNFα, and TNFα+LPS (20 ng/ml each trigger). UC organoids secreted significant higher levels of CXCL1 as detected in the media at baseline (p=0.02) and with IFNy+TNFa (p=0.01), but no difference was noted with TNFa+LPS (Fig. 1). In addition, CXCL1 mRNA showed significant higher levels after inflammatory triggering in UC vs. controls (Fig. 1) with IFNγ +LPS, (p=0.02), IFNγ+TNFα (p=0.003), and TNFα+LPS (p=0.016). Similarly, several other genes showed significant and substantial induction in UC organoids vs. controls, in some or all the inflammatory triggers (Fig. 2). The tight junction-associated protein, ZO1 showed substantially higher induction in UC compared to controls with the 3 inflammatory cocktails [IFNγ +LPS, (p=0.03), IFNγ+TNFα (p=0.02), and TNFα+LPS (p=0.005)]. Significantly higher expression in UC organoid was further noted in comparison to control in IL8 levels upon IFNγ +LPS (p=0.002), in interferon inducible IDO1 with IFNγ+TNFα (p=0.001), and in goblet associated MUC2 (p=0.04) and bacterial sensing DUOX2 (p=0.001) with TNFα+LPS. Conclusion Our data suggest that UC colonoids retain some inflammatory response activity in-vitro even after several passages. We show that UC organoids secrete higher level of CXCL1. Additionally, we note higher transcriptional response to different inflammatory signals in UC organoids potentially implying an “immune” epithelial transcriptional memory that may contribute to UC chronicity.
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Swierczek, Sabina, Soo Jin Kim, Mohamed E. Salama, William L. Heaton, Michael W. Deininger, and Josef T. Prchal. "Effect of a TNFα Blocker and Peginfa on Polycythemia Vera Clonal Hematopoiesis and Suppressed Normal Dormant Hematopoiesis." Blood 124, no. 21 (December 6, 2014): 1820. http://dx.doi.org/10.1182/blood.v124.21.1820.1820.
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Abstract Polycythemia vera (PV) is a clonal disorder arising from a single stem cell while normal stem cells are present in the marrow but are suppressed by the PV clone by an unknown mechanism. Pegylated interferon alfa-2a (PegInfa), a better-tolerated form of Infa induces clinical remission, reduces JAK2V617F allelic burden, and may convert clonal to polyclonal hematopoiesis (EL Liu, Blood 2003). Tumor necrosis factor-α (TNFa) levels are increased in patients with myeloproliferative neoplasms, including PV (Fleischman, Blood 2011). We previously reported that transcripts of TNFα mRNA are higher in CD34+ cells compared to more differentiated cells. TNFa is markedly reduced in those PegInfa-treated patients with decreased JAK2V617F allelic burden and/or return of polyclonal hematopoiesis (detected in females by X-chromosome allelic usage ratio), while no such decrease was seen in PV with hydroxyurea-induced normalization of elevated hematocrit/platelets/leukocytes (Swierczek, ASH 2012). To directly interrogate the role of TNFα in inducing suppression of normal hematopoiesis, we used a TNFα blocking antibody (adalimumab) and examined its role on PV erythropoiesis using a 3-week liquid culture system characterized by synchronized differentiation of expanding erythroid progenitors (Bruchova, Exp Hemat, 2007). In vitro expanded PV erythroid progenitors were grown with or without adalimumab or PegInfa. We evaluated apoptosis, proliferation and differentiation at different stages of erythroid maturation and correlated these parameters with TNFα transcripts, JAK2V617F allelic burden and, in females, clonality. Although the initial mononuclear cells represented a heterogeneous population, the expansion process favors erythroid progenitors and results in their synchronized differentiation. The JAK2V617F allelic burden increased concomitant with erythroid expansion and reached its peak at day 11 (when the majority of cells are proerythroblasts and basophilic erythroblasts), indicating a preferential expansion of erythroid progenitors, and then declined progressively. The addition of adalimumab markedly reduced TNFα mRNA and JAK2V617F allelic burden compared to controls. We previously reported that in this in vitro liquid expansion system, PV erythroid progenitors exhibit accelerated differentiation at days 7-14 and increased proliferation at days 9-14, with a larger S-phase population (40%) than controls (20%) at day 11 (Bruchova Exp Hemat, 2007). Compared to controls, adalimumab increased proliferation and delayed differentiation at early stages of PV erythropoiesis, with the proportion of apoptotic cells consistently decreased compared to erythroid cells expanded without adalimumab. Furthermore, X-chromosome-based clonality assays revealed preferential expansion of normal progenitors in 1 informative female patient. We also measured the impact of TNFα inhibition with adalimumab on burst-forming units-erythroid (BFU-E) colonies from PV patients cultured ex vivo. As expected, JAK2WT, JAK2WT/V617F and JAK2V617F BFU-E colonies were detected in cultures performed in the absence of adalimumab, while the addition of adalimumab preferentially abrogated JAK2V617F homozygous BFU-Es. In analogous experiments, PegInfa markedly decreased TNFα mRNA and JAK2V617F allelic burden, and decreased differentiation, but unlike adalimumab, it decreased proliferation and had no demonstrable effect on apoptosis. Ongoing studies are being performed to correlate the TNFα mRNA expression changes seen with adalimumab treatment in erythroid progenitors with differences in TNFα protein levels using intracellular cytokine staining and flow cytometry. These data suggest that blocking TNFα can suppress the JAK2V617F clone, rescue normal dormant hematopoiesis, and provide a foundation for a combined PV therapy using TNFα blockers with either PegInfa or JAK2 inhibitors. Disclosures Deininger: BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy.
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Wang, Chunli, Shuang Wang, Xuexue Lei, and Mingcui Zang. "CC Chemokine Ligand 17 Promoted Cell Metastasis via Tumor Necrosis Factorα/Nuclear Factor Kappa-B Signaling Pathway." Journal of Biomaterials and Tissue Engineering 11, no. 2 (February 1, 2021): 302–7. http://dx.doi.org/10.1166/jbt.2021.2540.
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Hepatocellular carcinoma (HCC) consist in a proinflammatory tumor environment that is characterized by the presence of many chemokines and cytokines. Expression of CCL17 associated with diagnoses and poor prognosis in different cancers. There are few investigations indicated the relationship between CCL17 and HCC. Thus, this study aims to investigate the role of CCL17 in HCC progression. qRT-PCR and Western Blot were performed to detect expression of CCL17 in HCC cell lines and normal hepatocyte. Elisa was used to determine TNFα, IL-6 and IL-1β. Wound-healing assay and Transwell assay were performed to assed cell metastasis. CCL17 signaling was examined utilizing Western Blot. Here, we showed that CCL17 levels markedly increased in HCC cell lines. At the same time, TNFα, IL-6 and IL-1 β were increased time-dependent after treating human recombinant CCL17 protein. Cell metastasis was significantly promoted by CCL17 while TNFa inhibitor (Lenalidomide) reversed the effects of CCL17. NF-κB signaling pathway was activated by CCL17 and TNFα inhibitor suppressed the effects of CCL17. In conclusion, CCL17 promoted cell metastasis via TNFα/NF-κB signaling pathway. CCL17 may be a potential biomarker for HCC progression.
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Idress, Mohannad, Bruce F. Milne, Gary S. Thompson, Laurent Trembleau, Marcel Jaspars, and Wael E. Houssen. "Structure-Based Design, Synthesis and Bioactivity of a New Anti-TNFα Cyclopeptide." Molecules 25, no. 4 (February 19, 2020): 922. http://dx.doi.org/10.3390/molecules25040922.
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As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein–protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide.
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Herbert, M. K., S. Hering, and P. Holzer. "Interleukin 1β, but not tumor necrosis factor, enhances neurogenic vasodilatation in the rat skin: involvement of nitric oxide." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 1075–79. http://dx.doi.org/10.1139/y95-153.
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In phenobarbitone-anesthetized rats the effects of interleukin 1β (IL-1β) and tumor necrosis factors (TNFs) were examined on die capsaicin-induced increase of plantar cutaneous blood flow in the rat hind paw as measured by laser Doppler flowmetry. IL-1β (0.5–500 pg) or TNFα or TNFβ (50–5000 pg) was injected subcutaneously into the left paws, while the right paws received vehicle (10 μL) only. IL-1β was without effect on blood flow by its own but dose dependency enhanced the hyperemia due to capsaicin (0.3 μg). TNFs failed to enhance the capsaicin-induced vasodilatation, although 5000 pg TNFα produced a transient increase of local blood flow. Indomethacin (10 mg/kg, i.p.) did not alter the capsaicin-induced vasodilatation but prevented IL-1β (50 pg) from augmenting the hyperemic response to capsaicin. Likewise, blockade of nitric oxide formation by NG-nitro-L-arginine methyl ester (L-NAME) failed to affect the capsaicin-evoked vasodilatation but abolished its amplification by IL-1β. Systemic pretreatment with a neurotoxic dose of capsaicin reduced the capsaicin-induced hyperemia and prevented the facilitatory effect of IL-1β. The hyperemia evoked by intraplantar calcitonin gene related peptide (0.038–3.8 ng) was not altered by IL-1β (50 pg). These data indicate that IL-1β but not TNF enhances the cutaneous hyperemic response to capsaicin. This proinflammatory action arises from sensitization of afferent nerve endings and depends on nitric oxide and cyclooxygenase products as essential intermediates.Key words: interleukin 1β, tumor necrosis factor, capsaicin, neurogenic inflammation, nitric oxide.
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Hessman, Christopher L., Josephine Hildebrandt, Aneri Shah, Sabine Brandt, Antonia Bock, Björn C. Frye, Ute Raffetseder, et al. "YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling." International Journal of Molecular Sciences 21, no. 19 (September 25, 2020): 7076. http://dx.doi.org/10.3390/ijms21197076.
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Inflammation and an influx of macrophages are common elements in many diseases. Among pro-inflammatory cytokines, tumor necrosis factor α (TNFα) plays a central role by amplifying the cytokine network. Progranulin (PGRN) is a growth factor that binds to TNF receptors and interferes with TNFα-mediated signaling. Extracellular PGRN is processed into granulins by proteases released from immune cells. PGRN exerts anti-inflammatory effects, whereas granulins are pro-inflammatory. The factors coordinating these ambivalent functions remain unclear. In our study, we identify Y-box binding protein-1 (YB-1) as a candidate for this immune-modulating activity. Using a yeast-2-hybrid assay with YB-1 protein as bait, clones encoding for progranulin were selected using stringent criteria for strong interaction. We demonstrate that at physiological concentrations, YB-1 interferes with the binding of TNFα to its receptors in a dose-dependent manner using a flow cytometry-based binding assay. We show that YB-1 in combination with progranulin interferes with TNFα-mediated signaling, supporting the functionality with an NF-κB luciferase reporter assay. Together, we show that YB-1 displays immunomodulating functions by affecting the binding of TNFα to its receptors and influencing TNFα-mediated signaling via its interaction with progranulin.
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Csiszar, Anna, Zoltan Ungvari, Akos Koller, John G. Edwards, and Gabor Kaley. "Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging." Physiological Genomics 17, no. 1 (March 12, 2004): 21–30. http://dx.doi.org/10.1152/physiolgenomics.00136.2003.
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Previously we demonstrated that aging in coronary arteries is associated with proinflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by enhancing endothelial apoptosis. To test this hypothesis we characterized proapoptotic alterations in the phenotype of coronary arteries of aged (26 mo old) and young (3 mo old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was an approximately fivefold increase in the number of apoptotic endothelial cells. In aged coronary arteries there was an increased expression of TNFα, TNFβ, and caspase 9 (microarray, real-time PCR), as well as increased caspase 9 and caspase 3 activity, whereas expression of TNFR1, TNFα-converting enzyme (TACE), Bcl-2, Bcl-X(L), Bid, Bax, caspase 8, and caspase 3 were unchanged. In vessel culture (18 h) incubation of aged coronary arteries with a TNF blocking antibody or the NO donor S-nitroso-penicillamine (SNAP) decreased apoptotic cell death. Incubation of young arteries with exogenous TNFα increased caspase 9 activity and elicited endothelial apoptosis, which was attenuated by SNAP. Inhibition of NO synthesis in cultured young coronary arteries also induced apoptotic cell death and potentiated the apoptotic effect of TNFα. Thus we propose that age-related upregulation of TNFα and caspase 9 and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to impaired endothelial function and ischemic heart disease in the elderly.
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Mori, Kouki, Katsumi Yoshida, Ayumi Komatsu, Jun-ichi Tani, Yoshinori Nakagawa, Saeko Hoshikawa, and Sadayoshi Ito. "Autoinduction of tumor necrosis factor-α in FRTL-5 rat thyroid cells." Journal of Endocrinology 187, no. 1 (October 2005): 17–24. http://dx.doi.org/10.1677/joe.1.05887.
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Tumor necrosis factor-α (TNFα) may play a role in the development of autoimmune thyroiditis such as Hashimoto’s thyroiditis. In the present study, we examined whether TNFα induced its own expression in FRTL-5 rat thyroid cells. Lipopolysaccharide (LPS) markedly increased TNFα mRNA levels in FRTL-5 cells as assessed by semiquantitative RT-PCR. In addition, LPS-stimulated cells released TNFα protein into the culture medium. Similarly, TNFα induced its own gene and protein expression in FRTL-5 cells as assessed by RT-PCR and metabolic labeling and immunoprecipitation of TNFα. The autoinduction of TNFα gene was also observed in TNFα-stimulated human thyroid epithelial cells. TNFα induction was specific to LPS and TNFα since interferon-α or amiodarone failed to increase TNFα mRNA levels in FRTL-5 cells. Human TNFα induced rat TNFα gene expression, indicating that type 1 TNF receptor (TNF-R) is involved in the autoinduction. TNFα did not increase either type 1 or type 2 TNF-R mRNA levels, suggesting that upregulation of TNF receptors is not involved in the autoinduction of TNFα. Although the biological significance of autoinduction of TNFα remains unclear, our results suggest that thyroid epithelial cells may participate in the development of autoimmune thyroiditis through production of TNFα. Furthermore, inhibition of TNFα production in the thyroid may represent a novel approach to mitigating inflammation in autoimmune thyroiditis.
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Croker, Ben A., O'Donnell A. Joanne, Donald Metcalf, Rickard James, Joseph Evans, Seth L. Masters, Andrew W. Roberts, Motti Gerlic, and John Silke. "Necroptotic Death Of RIPK1-Deficient HSC Compromises Hematopoiesis." Blood 122, no. 21 (November 15, 2013): 218. http://dx.doi.org/10.1182/blood.v122.21.218.218.
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Abstract Introduction Cell death can be triggered by many stimuli leading to apoptosis, pyroptosis (Caspase-1-dependent cell death) or necroptosis (Receptor-interacting serine/threonine-protein kinase (RIPK)-1/RIPK3-dependent cell death). RIPK1 is engaged by TNFR or Fas/CD95 ligation, and can induce NF-κB activation and cell death. FADD and Caspase-8 modulate RIPK1 and RIPK3 activity to prevent inappropriate induction of necroptosis (Oberst et al., Nature 2011, 471: 363-367; Zhang et al., Nature 2011, 471: 373-376). Modulation of necroptosis by small molecule inhibitors of RIPK1 has emerged as an exciting approach to intervene in inflammatory disease, ischemia reperfusion injury, pancreatitis and in mouse models of sepsis (He et al., Cell 2009, 137: 1100-1111; McNeal et al., Shock 2011, 35: 499-505; Oerlemans et al., Basic Res Cardiol 2012, 107: 270; Lukens et al., Nature 2013, 498: 224-227). However, RIPK1-deficient neonates die at birth and exhibit inflammatory disease and anemia, suggesting that inhibitors of RIPK1 may alter hematopoiesis. We have therefore investigated the hematological consequences of RIPK1 deficiency. Methods Fetal liver chimeras and competitive transplants were generated using E13.5 Ripk1-/-, Ripk3-/-and Ripk1-/-Ripk3-/- fetal liver cells. Serial transplants were established using 106 fetal liver cells for primary transplants and 0.2-5 x 106 bone marrow cells for secondary transplants. The survival of recipient mice and frequency of donor, competitor and recipient cells was assessed by flow cytometry up to 6 months post transplantation. The frequency of hematopoietic progenitor cells was assessed using in vitro clonal culture assays of E13.5-E18.5 fetal liver cells stimulated with SCF+IL-3+Epo in the presence or absence of TNFα or FasL. The contribution of TNFα and FasL to hematopoiesis was examined using TNFα neutralizing antibody in lethally-irradiated recipients of Ripk1-/- cells or by engrafting Ripk1-/- cells into lethally-irradiated Tnfa-/-Faslgld/gldrecipient mice. Results Ripk1 -/- fetal liver cells fail to engraft in lethally-irradiated recipients, with defects evident in lymphoid and myeloid lineages in the bone marrow, peripheral blood and spleen between 4 and 26 weeks post-transplant. In competitive fetal liver transplant experiments, Ripk1-/- hematopoietic stem and progenitor cells failed to compete with wild-type counterparts, indicating a cell-intrinsic defect in hematopoietic progenitor cells that cannot be attributed to the inflammatory disease evident in Ripk1-/- embryos. Ripk1-/- myeloid progenitor cells were sensitive to death induced by TNFα or FasL stimulation. Only minor abnormalities in hematopoiesis were detected when Ripk1-/- fetal liver cells were transplanted into lethally-irradiated Tnfa-/-Faslgld/gld recipient mice, or when lethally-irradiated wild-type recipient mice receiving Ripk1-/- fetal liver cells were treated with a TNFα neutralizing antibody, indicating key roles for TNFα and FasL during engraftment. A compound deficiency in RIPK3 rescued the reconstitution defects seen in Ripk1-/- cells suggesting that RIPK1-deficient hematopoietic cells undergo RIPK3-dependent necroptotic death. A residual defect in Ripk1-/-Ripk3-/-T lymphopoiesis suggests that RIPK1 deficiency induces other forms of cell death or that RIPK1 is required for other essential signaling pathways such as NF-κB signaling. Conclusion These data demonstrate essential roles for RIPK1 in hematopoiesis at steady state. Our results indicate that small molecule RIPK1 inhibitors should be used with caution in the clinic to avoid activation of RIPK3-dependent cell death pathways leading to cytopenia, immunosuppression and bone marrow failure. Finally, this work highlights that studies using RIPK1-deficient cells to study the roles for RIPK1 in inflammatory disease must draw conclusions with care considering the critical role of RIPK1 in hematopoiesis. Disclosures: No relevant conflicts of interest to declare.
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Gerasimova, Tatiana, Ekaterina Stepanenko, Lyudmila Novosadova, Elena Arsenyeva, Darya Shimchenko, Vyacheslav Tarantul, Igor Grivennikov, Valentina Nenasheva, and Ekaterina Novosadova. "Glial Cultures Differentiated from iPSCs of Patients with PARK2-Associated Parkinson’s Disease Demonstrate a Pro-Inflammatory Shift and Reduced Response to TNFα Stimulation." International Journal of Molecular Sciences 24, no. 3 (January 19, 2023): 2000. http://dx.doi.org/10.3390/ijms24032000.
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Parkinson’s disease (PD) is the second most common neurodegenerative diseases characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra. Mutations in the PARK2 gene are a frequent cause of familial forms of PD. Sustained chronic neuroinflammation in the central nervous system makes a significant contribution to neurodegeneration events. In response to inflammatory factors produced by activated microglia, astrocytes change their transcriptional programs and secretion profiles, thus acting as immunocompetent cells. Here, we investigated iPSC-derived glial cell cultures obtained from healthy donors (HD) and from PD patients with PARK2 mutations in resting state and upon stimulation by TNFα. The non-stimulated glia of PD patients demonstrated higher IL1B and IL6 expression levels and increased IL6 protein synthesis, while BDNF and GDNF expression was down-regulated when compared to that of the glial cells of HDs. In the presence of TNFα, all of the glial cultures displayed a multiplied expression of genes encoding inflammatory cytokines: TNFA, IL1B, and IL6, as well as IL6 protein synthesis, although PD glia responded to TNFα stimulation less strongly than HD glia. Our results demonstrated a pro-inflammatory shift, a suppression of the neuroprotective gene program, and some depletion of reactivity to TNFα in PARK2-deficient glia compared to glial cells of HDs.
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Li, Y., T. D. Nguyen, A. C. Stechschulte, D. J. Stechschulte, and K. N. Dileepan. "Effect of mast cell granules on the gene expression of nitric oxide synthase and tumour necrosis factor-α in macrophages." Mediators of Inflammation 7, no. 5 (1998): 355–61. http://dx.doi.org/10.1080/09629359890884.
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Previous studies have shown that mast cell granules (MCG) inhibit numerous macrophage functions including tumour cytotoxicity, superoxide and nitric oxide (NO) production, and FCγ2a receptor-mediated phagocytosis. In this study, the effect of MCG on macrophage TNFα and nitric oxide synthase (iNOS) mRNA expression, and the production and fate of TNFα were examined. Upon activation with LPS+IFNγ, macrophages expressed both TNFα and iNOS mRNA and produced both TNFα and NO. Co-incubation of LPS+IFNγ-activated macrophages with MCG resulted in dose-dependent inhibition of iNOS mRNA expression. TNFα production in the activated macrophages was decreased by MCG, which was associated with a reduction in TNFα mRNA expression. MCG were also capable of degrading both macrophage-generated and recombinant TNFα. The direct effect of MCG on TNFα was partially reversed by a mixture of protease inhibitors. These results demonstrate that MCG decrease the production of NO and TNFα by inhibiting macrophage iNOS and TNFα gene expression. Furthermore, MCG post-transcriptionally alter TNFα levels via proteolytic degradation.
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Kleidonas, Dimitrios, and Andreas Vlachos. "Scavenging Tumor Necrosis Factor α Does Not Affect Inhibition of Dentate Granule Cells Following In Vitro Entorhinal Cortex Lesion." Cells 10, no. 11 (November 19, 2021): 3232. http://dx.doi.org/10.3390/cells10113232.
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Neurons that lose part of their afferent input remodel their synaptic connections. While cellular and molecular mechanisms of denervation-induced changes in excitatory neurotransmission have been identified, little is known about the signaling pathways that control inhibition in denervated networks. In this study, we used mouse entorhino-hippocampal tissue cultures of both sexes to study the role of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) in denervation-induced plasticity of inhibitory neurotransmission. In line with our previous findings in vitro, an entorhinal cortex lesion triggered a compensatory increase in the excitatory synaptic strength of partially denervated dentate granule cells. Inhibitory synaptic strength was not changed 3 days after the lesion. These functional changes were accompanied by a recruitment of microglia in the denervated hippocampus, and experiments in tissue cultures prepared from TNF-reporter mice [C57BL/6-Tg(TNFa-eGFP)] showed increased TNFα expression in the denervated zone. However, inhibitory neurotransmission was not affected by scavenging TNFα with a soluble TNF receptor. In turn, a decrease in inhibition, i.e., decreased frequencies of miniature inhibitory postsynaptic currents, was observed in denervated dentate granule cells of microglia-depleted tissue cultures. We conclude from these results that activated microglia maintain the inhibition of denervated dentate granule cells and that TNFα is not required for the maintenance of inhibition after denervation.
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Gottsch, Michelle L., Edward A. Van Kirk, and William J. Murdoch. "Tumour necrosis factor alpha up-regulates matrix metalloproteinase-2 activity in periovulatory ovine follicles: metamorphic and endocrine implications." Reproduction, Fertility and Development 12, no. 2 (2000): 75. http://dx.doi.org/10.1071/rd00054.
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The collagenous matrix of the wall of periovulatory follicles is degraded and remodelled during ovulatory ovarian rupture and luteinization. Matrix metalloproteinase-2 (MMP-2) belongs to a family of zinc endopeptidases that cleave extracellular proteins; its primary substrate is the type IV collagen of basement membranes. Tumour necrosis factor α (TNFα) is a putative mediator of collagenolysis and ovulation. The objective of this investigation was to ascertain the regulatory role of TNFa on MMP-2 activity relevant to the folliculo-luteal transition in ewes. Luteal regression and the preovulatory surge of gonadotropins were induced by administration of prostaglandin F 2 α and gonadotropin-releasing hormone (GnRH) on Days 14 and 15.5 (= 0 h) of the oestrous cycle, respectively. Ovulation occurs from the dominant follicle approximately 24 h after GnRH. An immunocapture-activity assay was used to measure MMP-2 in follicular extracts. Bioactive MMP-2 increased from 0 to 20 to 40 h after GnRH. Enzyme was immunolocalized at 40 h to the connective tissue framework that invades the parenchyma of the formative corpus luteum. Activity of MMP-2 was up-regulated by incubation (20 h) of 0-h follicular explants with TNFα; this response was suppressed by the transcriptional inhibitor actinomycin D. Activity of MMP-2 was reduced when preovulatory follicular tissues were incubated (12-h explants for 6 h) with TNFα antiserum. Ovulation was blocked by intrafollicular injection of TNFα antiserum. Unruptured follicles luteinized, but were deficient in collagenous/vascularized trabeculae, and produced less progesterone than their control luteal counterparts. It is suggested that TNFα, via MMP-2 induction, contributes to the reorganization of an ovulatory follicle into a fully competent corpus luteum.
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Rekdal, Ø., Z. Konopski, J. S. Svendsen, J. O. Winberg, T. Espevik, and B. Østerud. "The TNF Receptors p55 and p75 Mediate Chemotaxis of PMN Induced by TNFα and a TNFα 36–62 Peptide." Mediators of Inflammation 3, no. 5 (1994): 347–52. http://dx.doi.org/10.1155/s0962935194000487.
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The present study was performed to examine whether residues 36–62 of TNFα contain the chemotactic domain of TNFα, and whether the p55 and p75 TNF receptors are involved in TNFα induced chemotaxis. The chemotactic effect of TNFα on PMN was inhibited by the mAbs Hrt-7b and Utr-1, against the p55 and p75 TNF receptors, respectively. Both receptors may therefore be required for mediating the chemotactic effect of TNFcz. The synthetic TNFα 36–62, similar to TNFα, had chemotactic effects on both PMN and monocytes. The chemotactic activity of the TNFα 36–62 peptide on PMN, was inhibited by Htr-7b, Utr-1 and soluble p55 receptor, which shows that the peptide possessed the ability to induce chemotaxis through the TNF receptors. In contrast to TNFα, the peptide did not show a cytotoxic activity against WEHI 164 flbrosarcoma cells. It is suggested that different domains of the TNFα molecule induce distinct biological effects.
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Fleischman, Angela G., Karl J. Aichberger, Samuel B. Luty, Thomas G. Bumm, Curtis L. Petersen, Shirin Doratotaj, Kavin B. Vasudevan, et al. "TNFα facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms." Blood 118, no. 24 (December 8, 2011): 6392–98. http://dx.doi.org/10.1182/blood-2011-04-348144.
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AbstractProinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2V617F expressing cells in MPN. We show that JAK2V617F kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2V617F allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2V617F-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2V617F expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2V617F-positive MPN. Altogether our data are consistent with a model where JAK2V617F promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.
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Weidong Du, Xueling Ma, and E. Marion Schneider. "A Direct Immunoassay Assessment of Streptavidin- and N-Hydroxysuccinimide-Modified Biochips in Validation of Serological TNFα Responses in Hemophagocytic Lymphohistiocytosis." Journal of Biomolecular Screening 13, no. 6 (July 2008): 515–26. http://dx.doi.org/10.1177/1087057108319642.
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The authors report 2 biochip platforms on gold manufactured by either nanoscale biotinylated self-assembled architectures to streptavidin surface or proteins containing free NH 2 groups to N-hydroxysuccinimide (NHS)—activated surfaces and investigated the potential application of tumor necrosis factor—α (TNFα) serodiagnosis of hemophagocytic lymphohistiocytosis (HLH). Interactions of TNFα antigen and TNFα antibody on the biochips were optimized using an indirect immunofluorescence method. Variation coefficients were 1.87% to 4.56% on the streptavidin biochip and 5.03% to 8.64% on the NHS biochip. The correlation coefficients ( r) in TNFα and TNFα antibody assays in HLH patients between the 2 biochip formats were 0.9623 and 0.9386 and the concordance frequencies were 92.2% and 96.1%, respectively. To detect plasma TNFα-receptor complexes (TNFR1 and R2) in HLH, a biochip assay strategy was developed. Plasma levels of TNFα, TNFα antibody, and TNFα-receptor complexes (TNFR1 and R2) were detected in plasmas from 42 HLH cases using streptavidin biochips. Frequencies of the biomarkers in the plasmas were 40.5% (17/42) for TNFα, 30.9% (13/42) for TNFα antibody, 28.6% (12/42) for TNFα—receptor 1 complex, and 26.1% (11/42) for TNFα—receptor 2 complex, respectively. The streptavidin biochip format was more sensitive than the NHS surface and was demonstrated to be a valuable tool to identify individual biomarker molecules and molecular complexes in sera and cell lysates and to track therapeutic progress of patients. ( Journal of Biomolecular Screening 2008:515-526)
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Hu, Shi, Shuaiyi Liang, Huaizu Guo, Dapeng Zhang, Hui Li, Xiaoze Wang, Weili Yang, et al. "Comparison of the Inhibition Mechanisms of Adalimumab and Infliximab in Treating Tumor Necrosis Factor α-Associated Diseases from a Molecular View." Journal of Biological Chemistry 288, no. 38 (August 13, 2013): 27059–67. http://dx.doi.org/10.1074/jbc.m113.491530.
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TNFα-targeting therapy with the use of the drugs Etanercept, Infliximab, and Adalimumab is used in the clinical treatment of various inflammatory and immune diseases. Although all of these reagents function to disrupt the interaction between TNFα and its receptors, clinical investigations showed the advantages of Adalimumab treatment compared with Etanercept and Infliximab. However, the underlying molecular mechanism of action of Adalimumab remains unclear. In our previous work, we presented structural data on how Infliximab binds with the E-F loop of TNFα and functions as a TNFα receptor-binding blocker. To further elucidate the variations between TNFα inhibitors, we solved the crystal structure of TNFα in complex with Adalimumab Fab. The structural observation and the mutagenesis analysis provided direct evidence for identifying the Adalimumab epitope on TNFα and revealed the mechanism of Adalimumab inhibition of TNFα by occupying the TNFα receptor-binding site. The larger antigen-antibody interface in TNFα Adalimumab also provided information at a molecular level for further understanding the clinical advantages of Adalimumab therapy compared with Infliximab.
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El-Ani, Dalia, Irena Philipchik, Hagit Stav, Moran Levi, Jordana Zerbib, and Asher Shainberg. "Tumor necrosis factor alpha protects heart cultures against hypoxic damage via activation of PKA and phospholamban to prevent calcium overload." Canadian Journal of Physiology and Pharmacology 92, no. 11 (November 2014): 917–25. http://dx.doi.org/10.1139/cjpp-2014-0092.
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This study aims to elucidate the mechanisms by which tumor necrosis factor alpha (TNFα) provides protection from hypoxic damage to neonatal rat cardiomyocyte cultures. We show that when intracellular Ca2+ ([Ca2+]i) levels are elevated by extracellular Ca2+ ([Ca2+]o) or by hypoxia, then TNFα decreased [Ca2+]i in individual cardiomyocytes. However, TNFα did not reduce [Ca2+]i after its increase by thapsigargin, (a SERCA2a inhibitor), indicating that TNFα attenuates Ca2+ overload through Ca2+ uptake by SERCA2a. TNFα did not reduce [Ca2+]i, following its elevation when [Ca2+]o levels were elevated in TNFα receptor knock-out mice. H-89, a protein kinase A (PKA) inhibitor, attenuated the protective effect of TNFα when the cardiomyoctyes were subjected to hypoxia, as determined by lactate dehydrogenase (LDH) and creatine kinase (CK) released and from the cardiomyocytes. Moreover, when the levels of [Ca2+]i were increased by hypoxia, H-89, but not KN93, (a calmodulin kinase II inhibitor), prevented the reduction in [Ca2+]i by TNFα. TNFα increased the phosphorylation of PKA in normoxic and hypoxic cardiomyoctes, indicating that the cardioprotective effect of TNFα against hypoxic damage was via PKA activation. Hypoxia decreased phosphorylated phospholamban levels; however, TNFα attenuated this decrease following hypoxia. It is suggested that TNFα activates phospholamban phosphorylation in hypoxic heart cultures via PKA to stimulate SERCA2a activity to limit Ca2+ overload.
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Tang, Kechun, George Murano, Harrieth Wagner, Leonardo Nogueira, Peter D. Wagner, Alisa Tang, Nancy D. Dalton, Yusu Gu, Kirk L. Peterson, and Ellen C. Breen. "Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation." Journal of Applied Physiology 114, no. 9 (May 1, 2013): 1340–50. http://dx.doi.org/10.1152/japplphysiol.00607.2012.
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Pulmonary TNFα has been linked to reduced exercise capacity in a subset of patients with moderate to severe chronic obstructive pulmonary disease (COPD). We hypothesized that prolonged, high expression of pulmonary TNFα impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNFα construct, TNFα was overexpressed throughout life in mouse lungs (SP-C/TNFα+). TNFα levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNFα+ mice, TNFα increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNFα+ mice. While increases in lung volume and airspace size induced by TNFα were comparable in both sexes, pulmonary hypertension along with lower body and muscle mass were evident only in male mice. Left ventricular (LV) function (cardiac output, stroke volume, LV maximal pressure, and LV maximal pressure dP/d t) was not altered by TNFα overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNFα+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1α mRNA and increase in atrogin-1 and MuRF1 expression also only in male mice. In situ gastrocnemius fatigue resistance, reflecting both oxygen availability and contractility, was decreased similarly in female and male SP-C/TNFα+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNFα are susceptible to exercise limitation, possibly due to muscle wasting and loss of the oxidative muscle phenotype, with protection in females possibly due to estrogen.
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Valladares, Amparo, Alberto M. Álvarez, Juan José Ventura, Cesar Roncero, Manuel Benito, and Almudena Porras. "p38 Mitogen-Activated Protein Kinase Mediates Tumor Necrosis Factor-α-Induced Apoptosis in Rat Fetal Brown Adipocytes*." Endocrinology 141, no. 12 (December 1, 2000): 4383–95. http://dx.doi.org/10.1210/endo.141.12.7843.
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Abstract Tumor necrosis factor-α (TNFα) induces apoptosis and cell growth inhibition in primary rat fetal brown adipocytes. Here, we examine the role played by some members of the mitogen-activated protein kinase (MAPK) superfamily. TNFα activates extracellular regulated kinase-1/2 (ERK1/2) and p38MAPK. Inhibition of p38MAPK by either SB203580 or SB202190 highly reduces apoptosis induced by TNFα, whereas ERK inhibition potentiates it. Moreover, cotransfection of an active MKK3 mutant and p38MAPK induces apoptosis. p38MAPK inhibition also prevents TNFα-induced cell cycle arrest, whereas MEK1 inhibition enhances this effect, which correlates with changes in proliferating cell nuclear antigen expression, but not in cyclin D1. c-Jun and activating transcription factor-1 are potential downstream effectors of p38MAPK and ERKs upon TNFα treatment. Thus, TNFα-induced c-Jun messenger RNA expression requires ERKs activation, whereas p38MAPK inhibition enhances its expression. In addition, TNFα-induced activating transcription factor-1 phosphorylation is extensively decreased by SB203580. However, TNFα- induced NF-κB DNA-binding activity is independent of p38MAPK and ERK activation. On the other hand, C/EBP homology protein does not appear to mediate the actions of TNFα, because its expression is almost undetectable and even reduced by TNFα. Finally, although TNFα induces c-Jun N-terminal kinase (JNK) activation, transfection of a dominant negative of either JNK1 or JNK2 had no effect on TNFα-induced apoptosis. These results suggest that p38MAPK mediates TNFα-induced apoptosis and cell cycle arrest, whereas ERKs do the opposite, and JNKs play no role in this process of apoptosis.
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Filip, R., S. Jarmakiewicz - Czaja, D. Piątek, J. Sztembis, A. Pękala, and W. Guz. "P707 Anti-TNFα therapy has no effect on bone mineral density in younger patients with inflammatory bowel disease: A single-centre observational study." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S572. http://dx.doi.org/10.1093/ecco-jcc/jjz203.835.
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Abstract Background Active inflammation negatively affects bone mineral density. Biological treatment, among others silences the excessive reaction of the immune system, which can also reduce the risk of osteoporosis. The aim of the study is to determine whether bone mineral density is higher in patients with biological therapy. Methods In total, 112 patients over 18 years of age with CD (Crohn’s Disease) or UC (Ulcerative colitis) were included in the study. The mean value age was 35 years. Patients who had received anti-TNFα therapy (biosimilar infliximab CT-P13 or adalimumab), and who underwent densitometric evaluation after two year treatment, were selected. Those who had never received anti-TNFα therapy were selected as controls. Information regarding age, sex, weight, duration of CD, use of glucocorticoids and bisphosphonates, and signs of disease activity at the time of densitometric measurement were collected. Bone mineral density was measured by dual-energy X-ray absorptiometry (DEXA) within femoral neck and lumbar spine. Results are reported as g/cm2 and presented either as Z-score or as a T-score. Results The study group has characterised a mean value BMI (Body Mass Index)—24. The group of patients with anti-TNFαα therapy showed an average T-score left femur −0.7744 (CD) and −0.4382 (UC), but without anti-TNFα therapy −0.6636 (CD) and −0.2208 (UC). The entire study group showed a mean value t-score left femur of −0.54286. There were no significant statistical differences between the examined groups and the effect of anti-TNFα therapy on BMI, T-score left femur, T-score L2–L4 Conclusion The results of the preliminary study assessing the effect of anti-TNFα therapy on bone mineral density among the two treatment groups (CD and UC) do not indicate significant differences after the introduction of such therapy
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Bishu, Shrinivas, Mohammed El Zaatari, Atsushi Hayashi, Guoqing Hou, Nicole Bowers, Jami Kinnucan, Beth Manoogian, et al. "CD4+ Tissue-resident Memory T Cells Expand and Are a Major Source of Mucosal Tumour Necrosis Factor α in Active Crohn’s Disease." Journal of Crohn's and Colitis 13, no. 7 (February 4, 2019): 905–15. http://dx.doi.org/10.1093/ecco-jcc/jjz010.
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Abstract Background and Aims Tumour necrosis factor [TNF]α- and IL-17A-producing T cells are implicated in Crohn’s disease [CD]. Tissue-resident memory T [TRM] cells are tissue-restricted T cells that are regulated by PR zinc finger domain 1 [PRDM1], which has been implicated in pathogenic Th17 cell responses. TRM cells provide host defence but their role in CD is unknown. We thus examined CD4+ TRM cells in CD. Methods Colon samples were prospectively collected at endoscopy or surgery in CD and control subjects. Flow cytometry and ex vivo assays were performed to characterise CD4+ TRM cells. Results CD4+ TRM cells are the most abundant memory T cell population and are the major T cell source of mucosal TNFα in CD. CD4+ TRM cells are expanded in CD and more avidly produce IL-17A and TNFα relative to control cells. There was a unique population of TNFα+IL-17A+ CD4+ TRM cells in CD which are largely absent in controls. PRDM1 was highly expressed by CD4+ TRM cells but not by other effector T cells. Suppression of PRDM1 was associated with impaired induction of IL17A and TNFA by CD4+ TRM cells Conclusions CD4+ TRM cells are expanded in CD and are a major source of TNFα, suggesting that they are important in CD. PRDM1 is expressed by TRM cells and may regulate their function. Collectively, this argues for prospective studies tracking CD4+ TRM cells over the disease course.
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Widowati, Wahyu, Diana Krisanti Jasaputra, Sutiman Bambang Sumitro, Mochammad Aris Widodo, Ervi Afifah, Rizal Rizal, Dwi Davidson Rihibiha, et al. "Direct and Indirect Effect of TNFα and IFNγ Toward Apoptosis in Breast Cancer Cells." Molecular and Cellular Biomedical Sciences 2, no. 2 (September 1, 2018): 60. http://dx.doi.org/10.21705/mcbs.v2i2.21.
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Background: Breast cancer (BC) is the leading cause of death cancer in women. Cancer therapies using TNFα and IFNγ have been recently developed by direct effects and activation of immune responses. This study was performed to evaluate the effects of TNFα and IFNγ directly, and TNFα and IFNγ secreted by Conditioned Medium-human Wharton’s Jelly Mesenchymal Stem Cells (CM-hWJMSCs) toward apoptosis of BC cells (MCF7).Materials and Methods: BC cells were induced by TNFα and IFNγ in 175 and 350ng/mL, respectively. CM-hWJMSCs were produced by co-culture hWJMSCs and NK cells that secreted TNFα, IFNγ, perforin (Prf1), granzyme B (GzmB) for treating BC cells. The BC cells were treated with CM-hWJMSCs in 50%. The expression of apoptotic genes Bax, p53, and the antiapoptotic gene Bcl-2 were determined using RT-PCR.Results: TNFα and IFNγ at concentration of 350 ng/mL induced higher Bax expression compared to 175 ng/mL. TNFα and IFNγ 350 ng/mL, 175 ng/mL induced p53 expression, whilst TNFα and IFNγ at 350 ng/mL decreased Bcl-2 expression. Perf1, GzmB, TNFα and IFNγ-containing CM-hWJMSCs induced significantly apoptosis percentage, induced Bax expression, but did not effect p53, Bcl-2 expression.Conclusion: TNFα and IFNγ directly induce Bax, p53, decrease Bcl-2 gene expression. The Prf1, GzmB, TNFα, IFNγ-containing CM-hWJMSCs induce apoptosis and Bax expression.Keywords: breast cancer, Wharton’s Jelly mesenchymal stem cells, TNFα, IFNγ
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Guarnieri, Giulia, Erica Sarchielli, Paolo Comeglio, Erika Herrera-Puerta, Irene Piaceri, Benedetta Nacmias, Matteo Benelli, et al. "Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts." International Journal of Molecular Sciences 21, no. 17 (August 25, 2020): 6128. http://dx.doi.org/10.3390/ijms21176128.
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TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.
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Broussard, Suzanne R., Robert H. MCCusker, Jan E. Novakofski, Klemen Strle, Wen Hong Shen, Rodney W. Johnson, Gregory G. Freund, Robert Dantzer, and Keith W. Kelley. "Cytokine-Hormone Interactions: Tumor Necrosis Factor α Impairs Biologic Activity and Downstream Activation Signals of the Insulin-Like Growth Factor I Receptor in Myoblasts." Endocrinology 144, no. 7 (July 1, 2003): 2988–96. http://dx.doi.org/10.1210/en.2003-0087.
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Abstract TNFα is elevated following damage to skeletal muscle. Here we provide evidence that TNFα acts on muscle cells to induce a state of IGF-I receptor resistance. We establish that TNFα inhibits IGF-I-stimulated protein synthesis in primary porcine myoblasts. Similar results were observed in C2C12 murine myoblasts, where as little as 0.01 ng/ml TNFα significantly inhibits protein synthesis induced by IGF-I. TNFα also impairs the ability of IGF-I to induce expression of a key myogenic transcription factor, myogenin. The inhibition by TNFα of IGF-I-induced protein synthesis and expression of myogenin is not due to direct killing of myoblasts by TNFα. Although IGF-I induces an approximately 19-fold induction in tyrosine phosphorylation of the β-chains of its receptor, TNFα does not inhibit this autophosphorylation. Instead, TNFα significantly reduces by approximately 50% IGF-I-stimulated tyrosine phosphorylation of two of the major downstream receptor docking molecules, insulin receptor substrate (IRS)-1 and IRS-2. These results establish that low picogram concentrations of TNFα acts on both porcine and murine myoblasts to impair tyrosine phosphorylation of both IRS-1 and IRS-2, but not the receptor itself. These data are consistent with the notion that very low physiological concentrations of TNFα interfere with both protein synthesis and muscle cell development by inducing a state of IGF-I receptor resistance.
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Behrens, Edward, Xiaohong Liu, Bruce Freedman, and Sheila Rao. "A CpG triggered Syk-Calcium-CaMKII signal directs the secretion of TNFα by innate immune cells (P6297)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 184.10. http://dx.doi.org/10.4049/jimmunol.190.supp.184.10.
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Abstract The kinase Syk is reported to regulate cytokine secretion in multiple and conflicted manners. We therefore examined Syk in regulating CpG DNA stimulated TNFα secretion. Secreted cytokines were measured by ELISA and surface cytokines by flow cytometry. Gene deletion was achieved with both Cre-Lox and shRNA methods. Deletion of Syk decreases CpG induced TNFα secretion while TNFα mRNA and intracellular protein levels remain normal. In contrast, IL-6 secretion is unaffected. CpG induced plasma membrane levels of TNFα are decreased in Syk deficiency, suggesting that Syk is important for TNFα intracellular trafficking. A downstream effector of Syk is calcium (Ca) flux mediated by PLCγ activation. Supporting a role for Ca in Syk mediated TNFα release, we show: 1) CpG stimulation triggers calcium flux only in Syk-sufficient cells, 2) silencing PLCγ2 phenocopies the TNFα defect of Syk-deficient cells, 3) forced Ca mobilization using ionomycin rescues the TNFα secretion defect in Syk-deficient cells. CpG-triggered phosphorylation of the calcium dependent kinase CaMKII is defective in Syk-deficient cells. CpG-induced TNFα secretion is defective in CaMKII-deficient cells, and is not rescued by ionomycin, suggesting that CaMKII is downstream in the pathway initiated by Syk signaling. These data suggest that CpG provides active signals for TNFα transcription and translation as well as intracellular trafficking, via a Syk-Ca-CaMKII axis, allowing for the fine-tuning of TNFα secretion.
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Natarajan, Nirvikalpa, Shelley Batts, Saurabh Gombar, Raj Manickam, Varun Sagi, Sharon G. Curhan, and Konstantina M. Stankovic. "Associations of Tinnitus Incidence with Use of Tumor Necrosis Factor-Alpha Inhibitors among Patients with Autoimmune Conditions." Journal of Clinical Medicine 12, no. 5 (March 1, 2023): 1935. http://dx.doi.org/10.3390/jcm12051935.
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Tumor necrosis factor-alpha (TNFα) may promote neuroinflammation prompting tinnitus. This retrospective cohort study evaluated whether anti-TNFα therapy influences incident tinnitus risk among adults with autoimmune disorders and no baseline tinnitus selected from a US electronic health records database (Eversana; 1 January 2010–27 January 2022). Patients with anti-TNFα had ≥90-day history pre-index (first autoimmune disorder diagnosis) and ≥180-day follow-up post-index. Random samples (n = 25,000) of autoimmune patients without anti-TNFα were selected for comparisons. Tinnitus incidence was compared among patients with or without anti-TNFα therapy, overall and among at-risk age groups or by anti-TNFα category. High-dimensionality propensity score (hdPS) matching was used to adjust for baseline confounders. Compared with patients with no anti-TNFα, anti-TNFα was not associated with tinnitus risk overall (hdPS-matched HR [95% CI]: 1.06 [0.85, 1.33]), or between groups stratified by age (30–50 years: 1 [0.68, 1.48]; 51–70 years: 1.18 [0.89, 1.56]) or anti-TNFα category (monoclonal antibody vs. fusion protein: 0.91 [0.59, 1.41]). Anti-TNFα was not associated with tinnitus risk among those treated for ≥6 months (hdPS-matched HR [95% CI]: 0.96 [0.69, 1.32]) or ≥12 (1.03 [0.71, 1.5]), or those with RA (1.16 [0.88, 1.53]). Thus, in this US cohort study, anti-TNFα therapy was not associated with tinnitus incidence among patients with autoimmune disorders.
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Usychenko, E. N., Yu I. Bazhora, E. M. Usychenko, and V. A. Gudz. "The association gene’s TNFα G(308) with quantity of TNFα and degree of liver’s fibrosis in patients with chronic hepatitis C." Reports of Vinnytsia National Medical University 22, no. 4 (December 28, 2018): 682–85. http://dx.doi.org/10.31393/reports-vnmedical-2018-22(4)-19.
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The data on the polymorphism of cytokine genes associated with individual reactivity on the effects of hepatitis C virus, predict the rate of progression of liver fibrosis. The purpose of this work is study the association of the polymorphic marker G308A of the TNFα gene with its quantitative content and degree of liver fibrosis in patients with chronic hepatitis C. A total of 100 patients with CSF were examined. The polymorphism of G308A gene’s TNFα was studied by amplification of the corresponding genome zones by PCR. The assessment of the degree of fibrosis was performed using the non-invasive Fibrotest method. The study of the quantity of TNFα cytokine in serum of patients was performed by ELISA. The distribution of genotypes on the investigated polymorphic loci was verified using Pearson's χ2 criterion. The frequencies of alleles and genotypes in the groups were compared using Pearson's χ2 criterion with Yates correction for continuity with the number of degrees of freedom 1. In order to detect the correlation dependencies between the individual parameters, the Spearman correlation coefficient was applied. It was found that a smaller degree of fibrosis was observed in carriers of the GG TNFα genotype, and a greater degree of fibrosis in the carriers of the genotype AA TNFα (moderate feedback between the degree of fibrosis and the genotypes of TNFα). The higher content of TNFα is noted in the carriers of the AA genotype TNFα, the lower content of TNFα - in the carriers of the GG TNFα genotype (moderate feedback between the TNFα genotypes and the TNFα content). It has been established that a higher TNFα content is observed in patients with F1-F0 fibrosis, a lower TNFα content in patients with F2-F3 fibrosis (a strong correlation between the degree of fibrosis and the amount of TNFα cytokine). It is assumed that the production of the cytokine is determined at the genetic level, and the severity of changes in the cytokine profile in chronic hepatitis C affects the course of the pathological process. An increase in the TNFα content in chronic hepatitis C may be a marker for significant morphological changes in the hepatic tissue and high activity of the inflammatory process.
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Yu, Seok-Yeong, Zhenhua Liu, Soonkyu Chung, and Young-Cheul Kim. "Obesity-Induced Tumor Necrosis Factor Alpha Suppresses In Vivo and In Vitro Retinoic Acid Synthesis and Fatty Acid Oxidation in Adipose Tissue." Current Developments in Nutrition 5, Supplement_2 (June 2021): 955. http://dx.doi.org/10.1093/cdn/nzab050_022.
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Abstract Objectives Obese adipose tissue (AT) is characterized by decreased fatty acid oxidation (FAO) and overexpression of tumor necrosis factor alpha (TNFα), a potent proinflammatory mediator of AT dysfunction and metabolic diseases. Several studies have shown that biosynthesis of retinoic acid (RA) from retinol (vitamin A) is suppressed in obese AT. RA has been identified as an agonist for peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), a critical inducer of FAO. The present study aimed to identify a potential mediator of suppressing RA synthesis and thus metabolic dysregulation by (1) evaluating the role of TNFa in tissue RA synthesis and metabolism in vivo and (2) investigating the potential roles of all trans-RA (ATRA) against TNFa-induced AT dysfunction in vitro. We hypothesized that altered retinoid metabolism in obese AT leads to AT dysfunction by reducing PPARβ/δ expression in adipocytes and macrophages. Methods Wild-type (WT) or TNFa knockout (KO) mice were fed a high-fat diet (HFD) or a low-fat diet (LFD) for 16 weeks. Selected serum biochemical parameters as well as expression of genes related to FAO and retinol metabolism were assessed by qPCR and Western Blot analysis. 3T3-L1 adipocytes and RAW264.7 macrophages were also employed to evaluate the effect of TNFa and ATRA on RA synthesis and pro-inflammatory responses. Results We found that RA concentration was significantly attenuated in epididymal AT from HFD-fed TNFa KO group concomitant with the upregulation of genes for RA synthesis (RDH10 & RALDH1) and PPARβ/δ compared to HFD-fed WT group. In 3T3-L1 adipocytes, TNFa treatment significantly inhibited RA synthesis from retinol and downregulated the expression of RDH10 & RALDH1 genes and FAO makers (PPARβ/δ protein and CPT1 mRNA). Furthermore, ATRA treatment significantly increased the expression of PPARβ/δ protein and CPT1 mRNA in TNFα-treated cells. In addition, ATRA significantly suppressed adipocyte-conditioned medium-induced inflammatory responses in RAW264.7 macrophages by increasing PPARβ/δ expression. Conclusions These findings suggest that TNFα overexpressed in obesity mediates AT dysfunction by impairing RA synthesis and ATRA may confer protection against obesity-induced metabolic comorbidities. Funding Sources This project was partially supported by the US Department of Agricultural Experiment Station (MAS00503).
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Roher, Nerea, Victor Samokhvalov, Mònica Díaz, Simon MacKenzie, Amira Klip, and Josep V. Planas. "The Proinflammatory Cytokine Tumor Necrosis Factor-α Increases the Amount of Glucose Transporter-4 at the Surface of Muscle Cells Independently of Changes in Interleukin-6." Endocrinology 149, no. 4 (December 27, 2007): 1880–89. http://dx.doi.org/10.1210/en.2007-1045.
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TNFα is a proinflammatory cytokine secreted by macrophages in response to bacterial infection. Recently new evidence has emerged suggesting that stressed or injured myocytes produce TNFα that then acts as an autocrine and/or paracrine mediator. TNFα receptors types 1 and 2 are present in skeletal muscle cells, and muscle cells can secrete, in addition to TNFα, other cytokines such as IL-1β or IL-6. Furthermore, the plasma concentration of TNFα is elevated in insulin-resistant states associated with obesity and type 2 diabetes. Here we show that TNFα increased the amount of glucose transporter (GLUT)-4 at the plasma membrane and also glucose uptake in the L6 muscle cell line stably expressing GLUT4 tagged with the c-myc epitope. Regardless of the state of differentiation of the L6 cells, TNFα did not affect the rate of proliferation or of apoptosis. The stimulatory effects of TNFα on cell surface GLUT4 and glucose uptake were blocked by nuclear factor-κB and p38MAPK pathway specific inhibitors (Bay 11-7082 and SB220025), and these two pathways were stimulated by TNFα. Furthermore, although TNFα increased IL-6 mRNA and protein expression, IL-6 did not mediate the effects of TNFα on cell surface GLUT4 levels, which also did not require de novo protein synthesis. The results indicate that TNFα can stimulate glucose uptake in L6 muscle cells by inducing GLUT4 translocation to the plasma membrane, possibly through activation of the nuclear factor-κB and p38MAPK signaling pathways and independently of the production of IL-6.