Pivotal roles of interleukin-6 in transmural inflammation in murine T cell transfer colitis
Pivotal roles of interleukin-6 in transmural inflammation in murine T cell transfer colitis
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DOI：
10.1189/jlb.0604328
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发表时间：
2004-12-01
影响因子：
5.5
通讯作者：
Mukaida, N
中科院分区：
文献类型：
--
作者：
Kitamura, K;Nakamoto, Y;Mukaida, N
正常黏膜免疫功能的破坏是引起炎症性肠病的主要原因之一。白细胞介素(IL)-6是一种在各种类型炎症中异常产生的促炎细胞因子，但其在炎症性肠病中的作用仍不清楚。因此，我们分析了IL-6在小鼠T细胞转移性结肠炎发病机制中的作用，其组织病理学类似于克罗恩病。CD4(+)CD45RB（高）T细胞转移到严重联合免疫缺陷小鼠体内，诱导T细胞和巨噬细胞浸润，随着结肠炎的发展，CC趋化因子受体（CCR）1、CCR2、CCR5、CXC趋化因子受体3及其配体、肿瘤坏死因子α、干扰素γ和IL-6的基因表达逐渐增强。与野生型小鼠相比，经il -6缺陷小鼠的CD4(+)CD45RB（高）T细胞移植的受体结肠炎的发生率显著降低，结肠炎的严重程度略有降低。此外，几种细胞因子、趋化因子和基质金属蛋白酶的基因表达在il -6缺陷小鼠来源的T细胞中显著降低。这些观察结果表明，T细胞来源的IL-6可能会增加几种促炎分子的基因表达，从而引起跨壁炎症。因此，IL-6可能是治疗克罗恩病跨壁炎症的一个有希望的靶点，克罗恩病可导致严重的并发症，如狭窄、裂隙和瘘管。
Breakdown of normal mucosal immunity is one of the major causes for inflammatory bowel disease. Interleukin (IL)-6 is a proinflammatory cytokine produced aberrantly in various types of inflammation, but its role in inflammatory bowel disease is still obscure. Hence, we analyzed the roles of IL-6 in the pathogenesis of murine T cell transfer colitis, whose histopathology resembles Crohn's disease. The transfer of CD4(+)CD45RB(high) T cells into severe combined immunodeficiency mice induced the infiltration of T cells and macrophages, and the gene expression of CC chemokine receptor (CCR)1, CCR2, CCR5, CXC chemokine receptor 3, their ligands, tumor necrosis factor-alpha, interferon-gamma, and IL-6 was progressively augmented as colitis developed. The incidence of transmural colitis was significantly reduced with a minimal decrease in the severity of colitis in recipients transferred with CD4(+)CD45RB(high) T cells derived from IL-6-deficient mice compared with those with wildtype mice. Moreover, the gene expression of several cytokines, chemokines, and matrix metalloproteinases was reduced significantly in recipients transferred with IL-6-deficient, mice-derived T cells. These observations suggested that T cell-derived IL-6 may augment the gene expression of several proinflammatory molecules, thereby causing transmural inflammation. Thus, IL-6 might be a promising target for treating transmural inflammation in Crohn's disease, which can lead to severe complications such as strictures, fissures, and fistulas.