title: Targeting pre-ligand assembly domain of TNFR1 ameliorates autoimmune diseases - an unrevealed role in downregulation of Th17 cells.
abstract: The pre-ligand assembly domain (PLAD) of tumor necrosis factor receptors mediates specific ligand-independent receptor assembly and subsequent signaling. However, the physiological role of PLAD in the regulation of TNFR-mediated immune responses in autoimmunity is still unclear. By using the recombinant PLAD.Fc protein to block TNFR1 assembly, we demonstrated that PLAD.Fc treatment significantly reduced the TNFR1-driving proinflammatory cytokines and protected NOD mice from diabetes. Strikingly, Th17 differentiation was significantly inhibited in PLAD.Fc-treated NOD and TNFR1-deficient mice, indicating a TNFR1-dependent Th17 development. PLAD.Fc-modulated effects on DCs, in terms of the downregulation of Th17-inducing cytokines, IL-6 and TGF-β, explained the potential mechanism for Th17 suppression. Finally, we provided an additional result that PLAD.Fc administration diminished the infiltration of Th17 cells in the central nervous system and ameliorated the experimental autoimmune encephalomyelitis in mice. Collectively, these data demonstrated that targeting PLAD of TNFR1 provides protection from autoimmune diseases through the downregulation of Th17 and suggested a therapeutic potential of PLAD-modulation in TNF-involved inflammatory diseases.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Neihu, Taipei 114, Taiwan.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Wang
authors.forename: Feng-Cheng
authors.initials: FC
authors.lastname: Chou
authors.forename: Shyi-Jou
authors.initials: SJ
authors.lastname: Chen
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
authors.forename: Deh-Ming
authors.initials: DM
authors.lastname: Chang
authors.forename: Huey-Kang
authors.initials: HK
authors.lastname: Sytwu
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D019169:Jurkat Cells; D051379:Mice; D016688:Mice, Inbred NOD; D058990:Molecular Targeted Therapy; D010957:Plasmids; D017434:Protein Structure, Tertiary; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology
chemical_list: D015850:Interleukin-6; C000598437:PLAD.Fc fusion protein; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta