Elevated IL-6 expression in CD4 T cells via PKCtheta and NF-kappaB induces Th2 cytokine production.

T helper (Th) cell differentiation is a key event to mount an appropriate immune response. Th1 and Th2 cells produce their signature cytokines IFN-gamma and IL-4, respectively. However, as we have reported, CD4 T cells selected by MHC class II-expressing thymocytes (T-CD4) produce both Th1 and Th2 type cytokines under Th1 differentiation conditions. Furthermore, the expression of Th2 cytokines in these cells is Stat6 independent. In the current study, we investigated the molecular mechanisms by which CD4 T cells produce Th2 cytokines under the Th1 differentiation condition. We observed that IL-6 is highly expressed in T-CD4 T cells, which is at least partly responsible for Th2 cytokine production by Th1 differentiated cells. The enhanced expression of IL-6 is downstream of constitutive phosphorylation of PKCtheta and high NF-kappaB activity. Neutralizing IL-6, blocking PKCtheta phosphorylation, or inhibiting NF-kappaB translocation diminished Th2 cytokine expression in Th1 cultures. Therefore, our study revealed that autocrine IL-6 production can induce Th2 cytokine production, and that PKCtheta and NF-kappaB are essential components in the induction of IL-6-mediated Th2 development.