Reverse signaling initiated from GITRL induces NF-κB activation through ERK in the inflammatory activation of macrophages
Reverse signaling initiated from GITRL induces NF-κB activation through ERK in the inflammatory activation of macrophages
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DOI：
10.1016/j.molimm.2007.05.013
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发表时间：
2008-01-01
影响因子：
3.6
通讯作者：
Lee, Won-Ha
中科院分区：
文献类型：
--
作者：
Bae, Eun Mi;Kim, Won-Jung;Lee, Won-Ha
糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白配体(GITRL)与其同源受体GITR相互作用。为了探讨GITRL在巨噬细胞促炎活化中的作用及GITRL诱导的信号通路，我们用抗GITRL单抗或GITR：Fc融合蛋白刺激巨噬细胞系THP-1和原代巨噬细胞，并分析其细胞反应。GITRL刺激可诱导促炎细胞因子和基质金属蛋白酶-9的表达，上调ICAM-1的表达水平，从而增强细胞的聚集和与细胞外基质蛋白的黏附。这些促炎介质的激活需要ERK1/2丝裂原活化蛋白激酶(MAPK)的激活，并受p38MAPK和JNK的负调控。免疫荧光分析检测到核因子-kappaB p50亚基的核转位，并被ERK抑制剂阻断，表明GITRL刺激诱导了ERK1/2的磷酸化，继而激活了核因子-kappaB。此外，在类风湿关节炎的炎症疾病标本中，检测到GITRL和GITR在巨噬细胞中的表达。这些观察结果提出了GITRL介导的巨噬细胞炎症激活参与炎症性疾病发病机制的可能性。(C)2007爱思唯尔有限公司。保留所有权利。
Glucocorticoid-induced TNF receptor family related protein ligand (GITRL) is known to interact with its cognate receptor GITR. In order to investigate the potential role of GITRL in the pro-inflammatory activation of macrophages and the signaling pathway induced by GITRL, we stimulated the macrophage cell line, THP-1, and primary macrophages with an anti-GITRL monoclonal antibody or a GITR:Fc fusion protein and analyzed the cellular responses. The stimulation of GITRL induced the expression of pro-inflammatory cytokines and matrix metalloproteinase (MMP)-9 and up-regulated ICAM-1 expression levels, which was responsible for enhanced cellular aggregation and adhesion to extracellular matrix proteins. The activation of these pro-inflammatory mediators required the activation of ERK1/2 mitogen-activated protein kinase (MAPK) and negatively regulated by p38 MAPK and JNK. Immunofluorescence analysis detected nuclear translocation of the NF-kappa B p50 subunit and this was blocked by ERK inhibitor, indicating that GITRL stimulation induced ERK1/2 phosphorylation and subsequent activation of NF-kappa B. Furthermore, the expression of GITRL and GITR was detected in macrophages in inflammatory disease specimens such as atherosclerotic plaques and synovial tissues of rheumatoid arthritis. These observations raise the possibility that the GITRL-mediated inflammatory activation of macrophages is involved in the pathogenesis of inflammatory diseases. (c) 2007 Elsevier Ltd. All rights reserved.