title: Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling.
abstract: Interleukin 17 (IL-17) plays critical roles in the pathogenesis of various autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE). How the signals triggered by this powerful inflammatory cytokine are controlled to avoid abnormal inflammatory responses is not well understood. In this study, we report that TRAF3 is a receptor proximal negative regulator of IL-17 receptor (IL-17R) signaling. TRAF3 greatly suppressed IL-17-induced NF-κB and mitogen-activated protein kinase activation and subsequent production of inflammatory cytokines and chemokines. Mechanistically, the binding of TRAF3 to IL-17R interfered with the formation of the receptor signaling activation complex IL-17R-Act1-TRAF6, resulting in suppression of downstream signaling. TRAF3 markedly inhibited IL-17-induced expression of inflammatory cytokine and chemokine genes in vivo and consequently delayed the onset and greatly reduced the incidence and severity of EAE. Thus, TRAF3 is a negative regulator of IL-17R proximal signaling.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.forename: Wen
authors.initials: W
authors.lastname: Pan
authors.forename: Peiqing
authors.initials: P
authors.lastname: Shi
authors.forename: Hanchao
authors.initials: H
authors.lastname: Gao
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.forename: Xinyang
authors.initials: X
authors.lastname: Song
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lihua
authors.initials: L
authors.lastname: Zhao
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
authors.forename: Youcun
authors.initials: Y
authors.lastname: Qian
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology*; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000502:physiology; D051379:Mice; D010446:Peptide Fragments / Q000502:physiology; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D048008:TNF Receptor-Associated Factor 3 / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology; D051193:Toll-Like Receptors / Q000502:physiology
chemical_list: C541130:ACT1 protein; D018031:Connexin 43; D007370:Interferon Type I; D020381:Interleukin-17; D010446:Peptide Fragments; D053722:Receptors, Interleukin-17; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D016753:Interleukin-10