Cutting edge: TNF receptor-associated factor 4 restricts IL-17-mediated pathology and signaling processes.
The effector T cell subset, Th17, plays a significant role in the pathogenesis of multiple sclerosis and of other autoimmune diseases. The signature cytokine, IL-17, engages the IL-17R and recruits the E3-ligase NF-κB activator 1 (Act1) upon stimulation. In this study, we examined the role of TNFR-associated factor (TRAF)4 in IL-17 signaling and Th17-mediated autoimmune encephalomyelitis. Primary cells from TRAF4-deficient mice displayed markedly enhanced IL-17-activated signaling pathways and induction of chemokine mRNA. Adoptive transfer of MOG35-55 specific wild-type Th17 cells into TRAF4-deficient recipient mice induced an earlier onset of disease. Mechanistically, we found that TRAF4 and TRAF6 used the same TRAF binding sites on Act1, allowing the competition of TRAF4 with TRAF6 for the interaction with Act1. Taken together, the results of this study reveal the necessity of a unique role of TRAF4 in restricting the effects of IL-17 signaling and Th17-mediated disease.
Department of Immunology, Cleveland Clinic, Cleveland, OH 44195, USA.
Jarod A
JA
Zepp
Caini
C
Liu
Wen
W
Qian
Ling
L
Wu
Muhammet F
MF
Gulen
Zizhen
Z
Kang
Xiaoxia
X
Li
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D053449:TNF Receptor-Associated Factor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
C098680:Il17a protein, mouse; D020381:Interleukin-17; D012333:RNA, Messenger; D053449:TNF Receptor-Associated Factor 4; C506368:Traf4 protein, mouse