Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction.

Abstract

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.

• Authors: Hideki Ogura, Masaaki Murakami, Yuko Okuyama, Mineko Tsuruoka, Chika Kitabayashi, Minoru Kanamoto, Mika Nishihara, Yoichiro Iwakura, Toshio Hirano
• Journal: Immunity (Immunity) Vol. 29 Issue 4 Pg. 628-36 (Oct 17 2008) ISSN: 1097-4180 [Electronic] United States
• PMID: 18848474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-17
• Interleukin-6
• NF-kappa B
• STAT3 Transcription Factor
• Socs3 protein, mouse
• Stat3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Cytokine Receptor gp130

Topics

• Animals
• Arthritis (immunology, metabolism)
• Autoimmunity
• Cytokine Receptor gp130 (immunology, metabolism)
• Encephalomyelitis, Autoimmune, Experimental (immunology, metabolism)
• Feedback, Physiological
• Fibroblasts (immunology, metabolism)
• Interleukin-17 (immunology, metabolism)
• Interleukin-6 (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• NF-kappa B (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (immunology, metabolism)