The two faces of IL-6 on Th1/Th2 differentiation.

Interleukin (IL)-6 is a cytokine produced by several cell types including antigen presenting cells (APC) such as macrophages, dendritic cells, and B cells. IL-6 is involved in the acute phase response, B cell maturation, and macrophage differentiation. Here, we discuss a novel function of IL-6: the control of T helper (Th) 1/Th2 differentiation. IL-6 promotes Th2 differentiation and simultaneously inhibits Th1 polarization through two independent molecular mechanisms. IL-6 activates transcription mediated by nuclear factor of activated T cells (NFAT) leading to production of IL-4 by nai;ve CD4(+) T cells and their differentiation into effector Th2 cells. While the induction of Th2 differentiation by IL-6 is dependent upon endogenous IL-4, inhibition of Th1 differentiation by IL-6 is IL-4- and NFAT-independent. IL-6 inhibits Th1 differentiation by upregulating supressor of cytokine signaling (SOCS)-1 expression to interfere with IFNgamma signaling and the development of Th1 cells. Since IL-6 is abundantly produced by APC, it is a likely source of early Th1/Th2 control during CD4(+) T cell activation. Thus, by using two independent molecular mechanisms, IL-6 plays a dual role in Th1/Th2 differentiation.