Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1

Interleukin 6 (IL-6) is a cytokine produced by immune and nonimmune cells and exhibits functional pleiotropy and redundancy. IL-6 plays an important role in the differentiation of several cell types. Here, we describe a novel function of IL-6: the negative regulation of CD4(+) Th1 cell differentiation. While IL-6-directed CD4(+) Th2 differentiation is mediated by IL-4, inhibition of Th1 differentiation by IL-6 is independent of IL-4. IL-6 upregulates suppressor of cytokine signaling 1 (SOCS1) expression in activated CD4(+) T cells, thereby interfering with signal transducer and activator of transcription 1 (STAT1) phosphorylation induced by interferon gamma (IFN gamma). Inhibition of IFN gamma receptor-mediated signals by IL-6 prevents autoregulation of IFN I gene expression by IFN gamma during CD4(+) T cell activation, thereby preventing Th1 differentiation. Thus, IL-6 promotes CD4(+) Th2 differentiation and inhibits Th1 differentiation by two independent molecular mechanisms.