TRIF Mediates Toll-like Receptor 5-induced Signaling in Intestinal Epithelial Cells
TRIF Mediates Toll-like Receptor 5-induced Signaling in Intestinal Epithelial Cells
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DOI：
10.1074/jbc.m110.158394
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发表时间：
2010-11-26
影响因子：
4.8
通讯作者：
Rhee, Sang Hoon
中科院分区：
文献类型：
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作者：
Choi, Yoon Jeong;Im, Eunok;Rhee, Sang Hoon
toll样受体（TLRs）与适配器分子（MyD88、Mal/TIRAP、TRAM和TRIF）结合，介导宿主-微生物相互作用的信号传导。例如，TLR4利用Mal/TIRAP-MyD88 （myd88依赖通路）和TRAM-TRIF （myd88独立通路）的结合。然而，已知鞭毛蛋白的特异性受体TLR5仅利用MyD88来引发炎症反应，并且尚未发现其他接头分子参与TLR5依赖性信号传导。在这里，我们发现TRIF参与介导tlr5诱导的核因子κ B （NF κ B）和丝裂原活化蛋白激酶（MAPKs），特别是JNK1/2和ERK1/2在肠上皮细胞中的活化。在人结肠上皮细胞中，鞭毛蛋白激活TLR5允许TLR5和TRIF之间的物理相互作用（NCM460），而在鞭毛蛋白刺激下TLR5不与TRAM相互作用。与对照细胞相比，TRIF-KO小鼠的原代肠上皮细胞和trif -沉默的NCM460细胞均显著降低了鞭毛蛋白诱导的NF κ B （p105和p65）、JNK1/2和ERK1/2的激活。然而，鞭毛蛋白对p38的激活在这些trif缺陷细胞中得以保留。trifo - ko肠上皮细胞在鞭毛蛋白作用下炎症因子（角质细胞来源的细胞因子、巨噬细胞炎性蛋白3 α和IL-6）的表达显著降低，而trifo - wt小鼠的对照细胞在鞭毛蛋白作用下的细胞因子表达强劲。与trift - wt小鼠相比，trift - ko小鼠能够抵抗体内肠道炎症反应：鞭毛蛋白介导的结肠炎症加重和葡聚糖硫酸钠诱导的实验性结肠炎。我们得出结论，除了MyD88外，TRIF还介导TLR5依赖性反应，从而调节鞭毛蛋白/TLR5结合引起的炎症反应。我们的研究结果表明，TRIF在通过肠道上皮TLR5调节宿主-微生物通讯中发挥重要作用。
Toll-like receptors (TLRs) associate with adaptor molecules (MyD88, Mal/TIRAP, TRAM, and TRIF) to mediate signaling of host-microbial interaction. For instance, TLR4 utilizes the combination of both Mal/TIRAP-MyD88 (MyD88-dependent pathway) and TRAM-TRIF (MyD88-independent pathway). However, TLR5, the specific receptor for flagellin, is known to utilize only MyD88 to elicit inflammatory responses, and an involvement of other adaptor molecules has not been suggested in TLR5-dependent signaling. Here, we found that TRIF is involved in mediating TLR5-induced nuclear factor kappa B (NF kappa B) and mitogen-activated protein kinases (MAPKs), specifically JNK1/2 and ERK1/2, activation in intestinal epithelial cells. TLR5 activation by flagellin permits the physical interaction between TLR5 and TRIF in human colonic epithelial cells (NCM460), whereas TLR5 does not interact with TRAM upon flagellin stimulation. Both primary intestinal epithelial cells from TRIF-KO mice and TRIF-silenced NCM460 cells significantly reduced flagellin-induced NF kappa B (p105 and p65), JNK1/2, and ERK1/2 activation compared with control cells. However, p38 activation by flagellin was preserved in these TRIF-deficient cells. TRIF-KO intestinal epithelial cells exhibited substantially reduced inflammatory cytokine (keratinocyte-derived cytokine, macrophage inflammatory protein 3 alpha, and IL-6) expression upon flagellin, whereas control cells from TRIF-WT mice showed robust cytokine expression by flagellin. Compare with TRIF-WT mice, TRIF-KO mice were resistant to in vivo intestinal inflammatory responses: flagellin-mediated exacerbation of colonic inflammation and dextran sulfate sodium-induced experimental colitis. We conclude that in addition to MyD88, TRIF mediates TLR5-dependent responses and, thereby regulates inflammatory responses elicited by flagellin/TLR5 engagement. Our findings suggest an important role of TRIF in regulating host-microbial communication via TLR5 in the gut epithelium.