Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells
Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells
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DOI：
10.4049/jimmunol.181.9.6536
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Straus, Daniel S.
中科院分区：
文献类型：
--
作者：
Lee, Jimmy W.;Wang, Ping;Straus, Daniel S.
IL-23/IL-17通路在慢性炎症性疾病（包括炎症性肠病）中起重要作用。在炎症性肠病中，肠上皮细胞是募集炎性细胞的趋化因子的重要来源。我们研究了IL-17对HT-29结肠上皮细胞趋化因子表达的影响。IL-17强烈抑制TNF-α刺激的CXCL 10、CXCL 11和CCL 5的表达，但与TNF-α协同诱导CXCL 8、CXCL 1和CCL 20 mRNA。对于CXCL 10，IL-17强烈抑制启动子活性，但对mRNA稳定性没有影响。相反，对于CXCL 8，IL-17略微降低启动子活性，但稳定其正常不稳定的mRNA，导致稳态mRNA丰度的净增加。IL-17与TNF-α协同反式激活表皮生长因子受体（EGFR）和激活ERK和p38 MAPK。p38和ERK通路抑制剂SB 203580和U 0126逆转了IL-17对CXCL 10 mRNA丰度和启动子活性的抑制作用，也逆转了IL-17对CXCL 8 mRNA的诱导作用，表明MAPK信号传导介导了IL-17对CXCL 10的转录抑制和CXCL 8 mRNA的稳定。EGFR激酶抑制剂AG 1478部分逆转了IL-17对CXCL 8和CXCL 10 mRNA的影响，证明EGFR在下游IL-17信号传导中的作用。总体结果表明IL-17对募集中性粒细胞（CXCL 8和CXCL 1）和Th 17细胞（CCL 20）的趋化因子具有积极作用。相比之下，IL-17抑制CXCL 10、CXCL 11和CCR 5的表达，这三种趋化因子选择性地募集Th 1而不是其他效应T细胞。免疫学杂志，2008，181：6536-6545.
The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-alpha-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-alpha for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-alpha in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells. The Journal of Immunology, 2008, 181: 6536-6545.