Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a Th17-independent manner

Naive CD4+ T cells rapidly proliferate to generate effector cells after encountering an antigen and small numbers survive as memory T cells in preparation for future immunological events. In the present work, adoptive transfer of naive CD4+ T cells into RAG2−/− mice caused the generation of memory-type effector T cells including Th1, Th2, Th17 and regulatory T cells, and eventually induced T cell-dependent colitis. We found here that blocking of the IL-6R with a specific mAb remarkably inhibited the CD4+ T cell-mediated colitis in parallel with the inhibition of Th17 cell generation. However, the transfer of naive CD4+ T cells prepared from IL-17−/− mice still induced severe colitis. At the effector phase, the mAb significantly inhibited IL-17 but not IFN-γ production. The blockade of IL-6 signaling enhanced the generation of IL-4- and IL-10-producing CD4+ T cells, and inhibited up-regulation of tumor necrosis factor -α mRNA expression in the colon. These findings clearly demonstrated that IL-6 is a critical factor for the induction of colitis by expansion of naive CD4+ T cells in RAG2−/− mice. Thus, the IL-6-mediated signaling pathway may be a significant therapeutic target in T cell-mediated autoimmune diseases.