scholarly journals HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160

2021 ◽  
Author(s):  
Weifeng Liu ◽  
Ting-Fang Chou ◽  
Sarah C. Garrett-Thomson ◽  
Goo-Young Seo ◽  
Elena Fedorov ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Types ◽  
Immune Functions ◽  
Liver Inflammation ◽  
Binding Partners ◽  
Ig Superfamily ◽  
Multiple Interactions ◽  
Necrosis Factor

HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM:LIGHT:CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knock-in mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.

scholarly journals HVEM structures and mutants reveal distinct functions of binding to LIGHT and BTLA/CD160

2021 ◽  
Vol 218 (12) ◽  
Author(s):  
Weifeng Liu ◽  
Ting-Fang Chou ◽  
Sarah C. Garrett-Thomson ◽  
Goo-Young Seo ◽  
Elena Fedorov ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Types ◽  
Immune Functions ◽  
Liver Inflammation ◽  
Binding Partners ◽  
Ig Superfamily ◽  
Multiple Interactions ◽  
Necrosis Factor

HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM–LIGHT–CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.

scholarly journals Expression of the Metalloproteinase ADAM8 Is Upregulated in Liver Inflammation Models and Enhances Cytokine Release In Vitro

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Tanzeela Awan ◽  
Aaron Babendreyer ◽  
Justyna Wozniak ◽  
Abid Mahmood Alvi ◽  
Viktor Sterzer ◽  
...  
Keyword(s):  
Cell Lines ◽  
Inflammatory Mediators ◽  
Liver Tissue ◽  
Stellate Cell ◽  
Hepatoma Cell ◽  
Cell Types ◽  
Chronic Liver ◽  
Liver Inflammation ◽  
Tnf Α

Acute and chronic liver inflammation is driven by cytokine and chemokine release from various cell types in the liver. Here, we report that the induction of inflammatory mediators is associated with a yet undescribed upregulation of the metalloproteinase ADAM8 in different murine hepatitis models. We further show the importance of ADAM8 expression for the production of inflammatory mediators in cultured liver cells. As a model of acute inflammation, we investigated liver tissue from lipopolysaccharide- (LPS-) treated mice in which ADAM8 expression was markedly upregulated compared to control mice. In vitro, stimulation with LPS enhanced ADAM8 expression in murine and human endothelial and hepatoma cell lines as well as in primary murine hepatocytes. The enhanced ADAM8 expression was associated with an upregulation of TNF-α and IL-6 expression and release. Inhibition studies indicate that the cytokine response of hepatoma cells to LPS depends on the activity of ADAM8 and that signalling by TNF-α can contribute to these ADAM8-dependent effects. The role of ADAM8 was further confirmed with primary hepatocytes from ADAM8 knockout mice in which TNF-α and IL-6 induction and release were considerably attenuated. As a model of chronic liver injury, we studied liver tissue from mice undergoing high-fat diet-induced steatohepatitis and again observed upregulation of ADAM8 mRNA expression compared to healthy controls. In vitro, ADAM8 expression was upregulated in hepatoma, endothelial, and stellate cell lines by various mediators of steatohepatitis including fatty acid (linoleic-oleic acid), IL-1β, TNF-α, IFN-γ, and TGF-β. Upregulation of ADAM8 was associated with the induction and release of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CX3CL1). Finally, knockdown of ADAM8 expression in all tested cell types attenuated the release of these mediators. Thus, ADAM8 is upregulated in acute and chronic liver inflammation and is able to promote inflammation by enhancing expression and release of inflammatory mediators.

scholarly journals Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling

2018 ◽  
Vol 215 (2) ◽  
pp. 501-519 ◽  
Author(s):  
Takashi Kanaya ◽  
Sayuri Sakakibara ◽  
Toshi Jinnohara ◽  
Masami Hachisuka ◽  
Naoko Tachibana ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Tumor Necrosis Factor Receptor ◽  
M Cells ◽  
M Cell ◽  
Antigen Uptake ◽  
Conditional Deletion ◽  
Follicle Associated Epithelium ◽  
Necrosis Factor

M cells are located in the follicle-associated epithelium (FAE) that covers Peyer’s patches (PPs) and are responsible for the uptake of intestinal antigens. The differentiation of M cells is initiated by receptor activator of NF-κB. However, the intracellular pathways involved in M cell differentiation are still elusive. In this study, we demonstrate that the NF-κB pathway activated by RANK is essential for M cell differentiation using in vitro organoid culture. Overexpression of NF-κB transcription factors enhances the expression of M cell–associated molecules but is not sufficient to complete M cell differentiation. Furthermore, we evaluated the requirement for tumor necrosis factor receptor–associated factor 6 (TRAF6). Conditional deletion of TRAF6 in the intestinal epithelium causes a complete loss of M cells in PPs, resulting in impaired antigen uptake into PPs. In addition, the expression of FAE-associated genes is almost silenced in TRAF6-deficient mice. This study thus demonstrates the crucial role of TRAF6-mediated NF-κB signaling in the development of M cells and FAE.

scholarly journals Fas-mediated apoptosis in cultured human eosinophils

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 2822-2830 ◽  
Author(s):  
A Druilhe ◽  
Z Cai ◽  
S Haile ◽  
S Chouaib ◽  
M Pretolani
Keyword(s):  
Tumor Necrosis Factor Receptor ◽  
Antigen Expression ◽  
Cell Types ◽  
Time Dependent ◽  
Cross Linking ◽  
Fas Antigen ◽  
Transmembrane Glycoprotein ◽  
Numerous Cell ◽  
Induced Apoptosis

Previous studies have shown that cytokine-dependent eosinophils undergo apoptosis, yet the mechanisms governing this phenomenon remain obscure. Fas antigen is a transmembrane glycoprotein belonging to the tumor necrosis factor receptor family. Cross-linking of Fas antigen in numerous cell types leads to apoptosis. In the present study, we examined the potential role of Fas antigen in the apoptosis of purified blood eosinophils from healthy donors. Cytokine-deprived eosinophils exhibited a time-dependent loss in viability, accompanied by an increase in the number of apoptotic nuclei and in the expression of Fas antigen and its mRNA, as shown by flow cytometry and reverse transcriptase-polymerase chain reaction, respectively. Cross-linking of Fas antigen with an agonistic anti-Fas monoclonal antibody (MoAb) induced a dose- and time-dependent increase in the number of apoptotic nuclei. Furthermore, using an in vitro coculture system, we showed engulfment of anti-Fas MoAb-treated eosinophils by monocyte-derived macrophages. Finally, incubation of eosinophils with the corticosteroid, dexamethasone, induced apoptosis and augmented that triggered by anti-Fas MoAb. Together, these observations suggest that Fas antigen expression and activation is involved in the apoptosis of human eosinophils and may contribute to the resolution of inflammatory allergic reactions in which eosinophil accumulation is a prominent feature.

scholarly journals SHIP limits immunoregulatory capacity in the T-cell compartment

Blood ◽  
2009 ◽  
Vol 113 (13) ◽  
pp. 2934-2944 ◽  
Author(s):  
Michelle M. Collazo ◽  
Daniela Wood ◽  
Kim H. T. Paraiso ◽  
Erin Lund ◽  
Robert W. Engelman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Necrosis Factor Receptor ◽  
Sh2 Domain ◽  
Graft Versus Host ◽  
Histocompatibility Complex ◽  
Delayed Rejection ◽  
Organ Graft ◽  
Necrosis Factor

Abstract Regulatory T cells (Tregs) play a pivotal role in preventing autoimmunity, graft-versus-host disease (GVHD), and organ graft rejection. We previously showed that either germline or induced SH2 domain–containing inositol 5-phosphatase (SHIP) deficiency in the host abrogates GVHD. Here we show that SHIP deficiency promotes an increase of CD4+CD25+FoxP3+ Tregs and CD4+CD25−FoxP3+“naive” T cells in the periphery that display increased CD103, glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR), OX40, and FcγRII/III expression. SHIP deficiency does not compromise Treg function because SHIP-deficient CD3+CD4+CD25+ Tregs are as suppressive as wild-type (WT) CD3+CD4+CD25+ Treg. Interestingly, like conventional Tregs, SHIP−/− CD4+CD25− T cells are unresponsive to major histocompatibility complex (MHC)–mismatched stimulators and suppress allogeneic responses by T cells in vitro. In addition, SHIP−/− CD4+CD25− T cells mediate reduced lethal GVHD on adoptive transfer to MHC-mismatched hosts. Furthermore, hosts with induced SHIP deficiency exhibit delayed rejection of MHC-mismatched cardiac grafts. Thus, SHIP is required for robust graft-versus-host and host-versus-graft responses by CD4+ T cell and limits their immunoregulatory capacity. These findings further define the immunosuppressive mechanisms that result from SHIP deficiency and provide additional justification for targeting SHIP in clinical transplantation.

Melittin attenuates liver injury in thioacetamide-treated mice through modulating inflammation and fibrogenesis

2011 ◽  
Vol 236 (11) ◽  
pp. 1306-1313 ◽  
Author(s):  
Ji-Hyun Park ◽  
Yoon-Seup Kum ◽  
Tae-Im Lee ◽  
Soo-Jung Kim ◽  
Woo-Ram Lee ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Liver Inflammation ◽  
Amphipathic Peptide ◽  
Bioactive Component ◽  
Factor Α ◽  
Necrosis Factor

Liver fibrosis represents a process of healing and scarring in response to chronic liver injury. Following injury, an acute inflammation response takes place resulting in moderate cell necrosis and extracellular matrix damage. Melittin, the major bioactive component in the venom of honey bee Apis mellifera, is a 26-residue amphipathic peptide with well-known cytolytic, antimicrobial and proinflammatory properties. However, the molecular mechanisms responsible for the anti-inflammatory activity of melittin have not been elucidated in liver fibrosis. We investigated whether melittin ameliorates liver inflammation and fibrosis in thioacetamide (TAA)-induced liver fibrosis. Two groups of mice were treated with TAA (200 mg/L, in drinking water), one of the groups of mice was co-treated with melittin (0.1 mg/kg) for 12 weeks while the other was not. Hepatic stellate cells (HSCs) were cultured with tumor necrosis factor α in the absence or presence of melittin. Melittin suppresses the expression of proinflammatory cytokines through the nuclear factor (NF)- κB signaling pathway. Moreover, melittin reduces the activity of HSCs in vitro, and decreases the expression of fibrotic gene responses in TAA-induced liver fibrosis. Taken together, melittin prevents TAA-induced liver fibrosis by inhibiting liver inflammation and fibrosis, the mechanism of which is the interruption of the NF- κB signaling pathway. These results suggest that melittin could be an effective agent for preventing liver fibrosis.

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