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SOCS1 mediates IL-6 effects
Arthritis Research & Therapyvolume 3, Article number: 68143 (2001)
Cytokines are the strongest regulators of T-cell differentiation. Interleukin (IL)-12 and interferon (IFN)-? drive Th1 differentiation whereas IL-4 promotes Th2 differentiation. It has been shown that IL-6 derived from antigen presenting cells initiates IL-4 production in naive CD4+ T cells which in turn polarizes them to the Th2 phenotype. In this study the mechanisms by which IL-6 inhibits Th1 cell differentiation were evaluated.
A negative effect of IL-6 on Th1 differentiation of CD4+ T cells was demonstrated in different in vitro systems and in vivo. IL-6 reduced the level of IFN-? production in the presence or absence of exogenous IL-12. The presence of anti-IL-4 antibody did not prevent the suppressive effect of IL-6. Interestingly, IL-6 did not influence IFN-? production by CD4+ T cells from mice deficient in IFN-? receptor a (IFN-?Ra). A decrease in IFN-?-induced STAT-1 phosphorylation in the presence of IL-6 was observed, suggesting that IL-6 might modulate Th1 differentiation by interfering with IFN-?R signaling. Consequently, the effect of IL-6 on IFN-? production by T cells deficient in suppressor of cytokine signalling 1 (SOCS1) and by wild-type cells was determined. While IL-6 inhibited IFN-? production by wild-type cells stimulated with anti-CD3 and anti-CD28, it failed to downregulate the production of IFN-? in SOCS1-deficient CD4+ T cells. Moreover, IL-6 inhibited STAT-1 phosphorylation in CD4+ T cells from IFN-?-/-SOCS1+/+ mice, but did not alter STAT-1 phosphorylation in T cells from IFN-?-/- SOCS1-/- mice.
IL-6 is produced by a variety of cell types such as macrophages, fibroblasts, endothelial cells, and activated T and B cells. IL-6 prevents resting T cells from undergoing apoptosis and regulates T-cell survival. Moreover, the systemic administration of IL-6 suppressed the development and the progression of experimental autoimmune encephalomyelitis, presumably by limiting the generation of Th1 effectors. The data in this study demonstrate that the negative effect of IL-6 on Th1 differentiation was independent of IL-4. IL-6 affected IFN-? production and IFN-?R signaling. Previous studies have demonstrated that IL-6-induced gene expression of the suppressor protein SOCS1 results in negative regulation of cytokine signaling. Thus, increased levels of SOCS1 might inhibit signaling triggered by IFN-?/IFN-?R ligation. In this regard, STAT-1 phosphorylation was prevented in CD4+ T cells from IFN-?-/- SOCS1+/+ transgenic mice. Together, the suppression of Th1 commitment by IL-6 is mediated by SOCS1 via interference with IFN-?R signaling, and the effect of IL-6 on Th2 differentiation results from the initiation of IL-4 production. Therefore, the result of the pleiotropic functions of IL-6 is the modulation of Th1 or Th2 differentiation by two completely independent mechanisms.
ELISA, RNase protection assay, electrophoretic mobility shift assay
Diehl S, Anguita J, Hoffmeyer A, Zapton T, Ihle JN, Rincon M: Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity. 2000, 13: 805-815.