TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice
TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice
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DOI：
10.1038/mi.2013.10
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发表时间：
2013-11-01
影响因子：
8
通讯作者：
Dohi, T.
中科院分区：
文献类型：
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作者：
Son, A.;Oshio, T.;Dohi, T.
肿瘤坏死因子（TNF）样弱凋亡诱导因子（TWEAK）是TNF超家族成员，在急性结肠炎模型中通过其受体Fn 14诱导上皮细胞（EC）损伤和炎症介质的产生。在我们目前的研究慢性结肠炎诱导的重复直肠注射的半抗原，我们发现，炎症，纤维化和辅助性T细胞2（Th 2）型免疫显着减少Fn 14基因敲除（KO）小鼠相比，野生型（WT）对照小鼠。胸腺基质淋巴细胞生成素（TSLP）在Fn 14 KO结肠EC中的表达低于WT EC。TWEAK在来自WT的结肠外植体中增强白细胞介素-13（IL-13）对TSLP的诱导，但在Fn 14 KO组织中不增强。TSLP受体KO小鼠表现出与Fn 14 KO小鼠相似的轻度慢性结肠炎。TWEAK和IL-13协同促进成纤维细胞增殖。因此，我们提出IL-13-TWEAK/Fn 14-TSLP轴作为慢性结肠炎伴纤维化的关键机制。
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a TNF superfamily member, induces damage of the epithelial cells (ECs) and production of inflammatory mediaters through its receptor Fn14 in a model of acute colitis. In our current study of chronic colitis induced by repeated rectal injection of a hapten, we found that inflammation, fibrosis, and T helper 2 (Th2)-type immunity were significantly reduced in Fn14 gene knockout (KO) mice when compared with wild-type (WT) control mice. Expression of thymic stromal lymphopoietin (TSLP) was lower in Fn14 KO colon ECs than in WT ECs. TWEAK potentiates the induction of TSLP by interleukin-13 (IL-13) in colon explants from WT but not in Fn14 KO tissue. TSLP receptor KO mice exhibit milder chronic colitis, similar to that in Fn14 KO mice. TWEAK and IL-13 synergistically promote fibroblast proliferation. Thus we propose an IL-13-TWEAK/Fn14-TSLP axis as a key mechanism underlying chronic colitis with fibrosis.