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

Immunity. 2008 Oct 17;29(4):628-36. doi: 10.1016/j.immuni.2008.07.018. Epub 2008 Oct 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / immunology
  • Arthritis / metabolism
  • Autoimmunity*
  • Cytokine Receptor gp130 / immunology
  • Cytokine Receptor gp130 / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Feedback, Physiological
  • Fibroblasts / immunology*
  • Fibroblasts / metabolism
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-6 / immunology
  • Interleukin-6 / 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
  • Suppressor of Cytokine Signaling Proteins / metabolism*


  • 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