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International Immunology Advance Access published online on November 1, 2007
International Immunology, doi:10.1093/intimm/dxm114
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

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

Daisuke Noguchi1, Daiko Wakita1, Masaki Tajima1, Shigeru Ashino1, Yoichiro Iwakura2, Yue Zhang3, Kenji Chamoto1, Hidemitsu Kitamura1 and Takashi Nishimura1,3

1 Division of Immunoregulation Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan
2 Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
3 Division of ROYCE' Health Bioscience, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan

Correspondence to: Correspondence to: T. Nishimura; E-mail: tak24{at}igm.hokudai.ac.jp

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-{gamma} 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 -{alpha} 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.

Keywords: colitis, IL-6, Th1, Th17

Transmitting editor: A. Falus

Received 31 July 2007, accepted 5 October 2007.


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