Novel role of IL-6/SIL-6R signaling in the expression of inducible nitric oxide synthase (iNOS) in murine B16, metastatic melanoma clone F10.9, cells
Novel role of IL-6/SIL-6R signaling in the expression of inducible nitric oxide synthase (iNOS) in murine B16, metastatic melanoma clone F10.9, cells
复制标题
DOI：
10.1016/j.freeradbiomed.2006.10.034
复制
发表时间：
2007-01-15
影响因子：
7.4
通讯作者：
Oh, Jae-Wook
中科院分区：
文献类型：
--
作者：
Kang, Keon Wook;Wagley, Yadav;Oh, Jae-Wook
诱导型一氧化氮合酶（iNOS）已被证明是经常在黑色素瘤表达，这种酶的上调，虽然是与肿瘤的进展。在这项研究中，我们研究了不同的细胞因子，如：IL-6，TNF-α，IL-1 β，IFN-γ和IL-6 RIL 6（IL-6 R（sIL-6 R）和IL-6的可溶性形式的高活性融合蛋白）是否增强B16/F10.9小鼠转移性黑色素瘤细胞中iNOS基因的表达。IL 6 RIL 6 + TNF-α联合治疗可增加iNOS表达和NO生成。凝胶位移和报告基因分析显示，IL 6 RIL 6选择性激活AP-1，而TNF-α增加NF-κ B和AP-1的活性。在用IL 6 RIL 6加TNF-α处理的细胞中也观察到AP-1的持续活化。用IL 6 RIL 6/TNF-α刺激细胞导致促分裂原活化蛋白激酶（MAPK）如c-Jun N-末端激酶（JNK）和p38的活化，以及用JNK或p38 MAPK抑制剂预处理的废除。IL 6 RIL 6或IL 6 RIL 6/TNF α诱导的AP-1结合增加被抗c-Jun或c-Fos抗体超移，并且c-Jun和c-Fos的激活分别依赖于JNK和p38。这些结果表明，IL-6/sIL-6 R/gp 130复合信号通过JNK/p38 MAPK介导的AP-1激活对黑色素瘤细胞中iNOS基因表达具有意想不到的积极作用。(c)2006年爱思唯尔公司All rights reserved.
Inducible nitric oxide synthase (iNOS) has been shown to be frequently expressed in melanomas; up-regulation of this enzyme is though to be associated with tumor progression. In this study, we investigated whether diverse cytokines such as: IL-6, TNF-alpha, IL-1 beta, IFN-gamma and IL6RIL6 (a highly active fusion protein of the soluble form of the IL-6R (sIL-6R) and IL-6) enhance the iNOS gene expression in B16/F10.9 murine metastatic melanoma cells. An increase at iNOS expression and NO production was observed with the co-treatment of IL6RIL6 plus TNF-a. Gel shift and reporter gene analyses revealed that IL6RIL6 selectively activated AP-1; while TNF-a increased the activities of both NF-kappa B and AP-1. Persistent activation of AP-1 was also seen in cells treated with IL6RIL6 plus TNF-a. Stimulation of cells with IL6RIL6/TNF-alpha resulted in the activation of mitogen-activated protein kinases (MAPK) such as c-Jun N-terminal kinase (JNK) and p38, and the abrogation by pretreatment with JNK or p38 MAPK inhibitor. IL6RIL6 or IL6RIL6/TNF alpha-inducible AP-1 binding increase was supershifted by anti-c-Jun or c-Fos antibodies, and the activation of c-Jun and c-Fos was dependent on JNK and p38, respectively. These results suggest that IL-6/sIL-6R/gp130 complex signaling has an unexpected positive effect on iNOS gene expression through JNK/p38 MAPK tnediated-AP-1 activation in melanoma cells. (c) 2006 Elsevier Inc. All rights reserved.