Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.
Dysregulated cytokine expression and signaling are major contributors to a number of autoimmune diseases. Interleukin-17A (IL-17A) and IL-6 are important in many disorders characterized by immune self-recognition, and IL-6 is known to induce the differentiation of T helper 17 (Th17) cells. Here we described an IL-17A-triggered positive-feedback loop of IL-6 signaling, which involved the activation of the transcription factors nuclear factor (NF)-kappaB and signal transducer and activator of transcription 3 (STAT3) in fibroblasts. Importantly, enhancement of this loop caused by disruption of suppressor of cytokine signaling 3 (SOCS3)-dependent negative regulation of the IL-6 signal transducer gp130 contributed to the development of arthritis. Because this mechanism also enhanced experimental autoimmune encephalomyelitis (EAE) in wild-type mice, it may be a general etiologic process underlying other Th17 cell-mediated autoimmune diseases.
Ogura
Hideki
H
Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Murakami
Masaaki
M
Okuyama
Yuko
Y
Tsuruoka
Mineko
M
Kitabayashi
Chika
C
Kanamoto
Minoru
M
Nishihara
Mika
M
Iwakura
Yoichiro
Y
Hirano
Toshio
T
D000818:Animals; D001168:Arthritis / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D050822:Cytokine Receptor gp130 / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism*
D020381:Interleukin-17; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D050822:Cytokine Receptor gp130