Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation:: Evidence in Crohn disease and experimental colitis in vivo
Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation:: Evidence in Crohn disease and experimental colitis in vivo
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DOI：
10.1038/75068
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发表时间：
2000-05-01
期刊：
影响因子：
82.9
通讯作者：
Neurath, MF
中科院分区：
文献类型：
--
作者：
Atreya, R;Mudter, J;Neurath, MF
促炎细胞因子白细胞介素（IL）-6（refs. 1-5)当与可溶性IL-6受体（sIL-6 R）形成复合物时，可与缺乏IL-6受体（IL-6 R）的细胞结合（反式信号传导）（5-7）。在此，我们评估了该系统对克罗恩病（CD）（一种胃肠道慢性炎性疾病）中粘膜T细胞抗凋亡的抵抗力增加的贡献（8-12）。针对IL-6 R的中和抗体通过诱导固有层T细胞的凋亡，抑制由1型T辅助细胞介导的CD的各种动物模型中建立的实验性结肠炎。类似地，新设计的gp 130-Fc融合蛋白在体内特异性中和sIL-6 R导致结肠炎活动的抑制和细胞凋亡的诱导，表明sIL-6 R防止粘膜T细胞凋亡。在Co患者中，粘膜T细胞显示出IL-6反式信号传导的强有力证据，信号转导子和转录激活子3、bcl-2和bcl-xl被激活。阻断IL-6反式信号通路可导致T细胞凋亡，表明IL-6-sIL-6 R系统介导CD中T细胞对凋亡的抵抗。这些数据表明，由IL-6-sIL-6 R驱动的T细胞活化途径有助于慢性肠道炎症的持续存在。特异性靶向该通路可能是治疗CD的一种有前途的新方法。
The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling)(5-7). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract(8-12). A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with Co, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.