Immunology IL-6 SOCS It to Th1 Differentiation

The differentiation of naïve CD4⁺ T cells into Th1 and Th2 subtypes is mediated by specific cytokines. For example, interleukin 6 (IL-6) can increase the production of IL-4, a cytokine that mediates naïve T cell differentiation into the Th2 pathway, whereas IL-12 and interferon (IFN-) cause Th1 differentiation. However, the negative regulation of T cell differentiation is less well understood. Diehl et al. showed that IL-6, independent of IL-4, can negatively regulate Th1 differentiation by shutting off IFN- signaling. IL-12-treated naïve CD4⁺ cells in the presence of IL-6 and an IL-4 neutralizing antibody, were defective for Th1 differentiation. In vivo, mice infected with the spirochete Borrelia burgdorferi and treated with IL-6 had lower levels of IFN-, probably because of decreased IFN- transcription. Even in the presence of exogenous IFN-, T cells treated with IL-6 and neutralizing IL-4 antibody produced lower levels of IFN-, indicating that IL-6 interferes with the positive feedback loop of IFN- production. IL-6 treatment of T cells increased the expression of SOCS1 (suppressor of cytokine signaling 1), a protein that blocks STAT activation by inhibiting upstream Janus kinase activity. T cells treated with IFN- in the presence of IL-6 contained little activated STAT1, a transcription factor required for IFN- gene expression. IL-6 treatment of SOCS1-deficient cells led to no inhibition of IFN- production, suggesting that IL-6 inhibition of IFN- production and signaling is mediated through SOCS1. Thus, IL-6 promotes Th2 cell differentiation while inhibiting differentiation into Th1 cells.

Diehl, S., Anguita, J., Hoffmeyer, A., Zapton, T., Ihle, J.N., Fikrig, E., and Rincón, M. (2000) Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 13: 805-815. [Online Journal]