Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a T(h)17-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 T(h)1, T(h)2, T(h)17 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 T(h)17 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.
Noguchi
Daisuke
D
Division of Immunoregulation Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Wakita
Daiko
D
Tajima
Masaki
M
Ashino
Shigeru
S
Iwakura
Yoichiro
Y
Zhang
Yue
Y
Chamoto
Kenji
K
Kitamura
Hidemitsu
H
Nishimura
Takashi
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003092:Colitis / Q000276:immunology*; D003106:Colon / Q000276:immunology; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D020381:Interleukin-17; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma