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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.