Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a Th17-independent manner
Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a Th17-independent manner
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DOI：
10.1093/intimm/dxm114
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Nishimura, Takashi
中科院分区：
文献类型：
--
作者：
Noguchi, Daisuke;Wakita, Daiko;Nishimura, Takashi
初始CD 4（+）T细胞在遇到抗原后迅速增殖以产生效应细胞，并且小数量作为记忆T细胞存活，为未来的免疫事件做准备。在本工作中，将幼稚CD 4（+）T细胞过继转移到RAG 2（-/-）小鼠中，导致记忆型效应T细胞（包括T（h）1、T（h）2、T（h）17和调节性T细胞）的产生，并最终诱导T细胞依赖性结肠炎。我们发现，用特异性mAb阻断IL-6 R可显著抑制CD 4（+）T细胞介导的结肠炎，同时抑制T（h）17细胞的生成。然而，从IL-17（-/-）小鼠制备的初始CD 4（+）T细胞的转移仍然诱导严重的结肠炎。在效应期，mAb显著抑制IL-17但不抑制IFN-γ的产生。IL-6信号的阻断增强了产生IL-4和IL-10的CD 4（+）T细胞的生成，并抑制了结肠中肿瘤坏死因子-α mRNA表达的上调。这些发现清楚地表明，IL-6是RAG 2（-/-）小鼠中初始CD 4（+）T细胞扩增诱导结肠炎的关键因素。因此，IL-6介导的信号通路可能是T细胞介导的自身免疫性疾病的重要治疗靶点。
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.