Protein tyrosine kinase inhibitors block tumor necrosis factor-induced activation of nuclear factor-κB, degradation of IκBα, nuclear translocation of p65, and subsequent gene expression
Protein tyrosine kinase inhibitors block tumor necrosis factor-induced activation of nuclear factor-κB, degradation of IκBα, nuclear translocation of p65, and subsequent gene expression
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蛋白酪氨酸激酶抑制剂阻断肿瘤坏死因子诱导的核因子-κB 激活、IκBα 降解、p65 核转位以及随后的基因表达
DOI：
10.1006/abbi.1998.0576
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发表时间：
1998
影响因子：
3.9
通讯作者：
B. Aggarwal
中科院分区：
文献类型：
--
作者：
Kaushik Natarajan;S. Manna;M. Chaturvedi;B. Aggarwal
摘要已知肿瘤坏死因子的多种炎症作用是通过核转录因子NF-κB的激活来实现的，但肿瘤坏死因子如何激活核转录因子-κB尚不完全清楚。在本报告中，我们用蛋白酪氨酸激酶的两种有效的抑制剂金雀异黄素和erbstatin研究了蛋白酪氨酸激酶在肿瘤坏死因子介导的NF-κB激活中的作用。用任何一种抑制剂处理人髓系U-937细胞，均以剂量和时间依赖的方式完全抑制肿瘤坏死因子诱导的NF-κB激活。抑制作用与PTK活性有关，因为在金雀异黄素的结构类似物中，只有PTK的活性抑制剂，槲皮素能阻断肿瘤坏死因子诱导的NF-κB的激活，而不能阻断非活性的大豆苷元。与T细胞和上皮细胞一样，对NF-κB活性的抑制并不局限于髓系细胞。两种蛋白酪氨酸激酶抑制剂均可抑制核因子-κB抑制亚基I-αB的降解和p65亚基的易位，但对p50和c-κ无明显影响。PTK抑制剂不干扰核因子-κB与DNA的结合。瞬时转染实验中依赖于NF-κB的CAT报告基因的表达也被PTK抑制剂抑制。两种PTK抑制剂均可阻断肿瘤坏死因子诱导的N端c-jun激酶和丝裂原活化蛋白激酶的激活。总之，我们的结果表明，金雀异黄素和erbstatin敏感的蛋白酪氨酸激酶参与了导致肿瘤坏死因子-κB激活和基因表达的途径，因此可以作为抗炎药物开发的靶点。
Abstract Several inflammatory effects of tumor necrosis factor (TNF) are known to be mediated through activation of a nuclear transcription factor NF-κB, but how TNF activates NF-κB is incompletely understood. In the present report, we examined the role of protein tyrosine kinases (PTK) in TNF-mediated NF-κB activation by using genistein and erbstatin, two potent inhibitors of PTK. The treatment of human myeloid U-937 cells with either inhibitor completely suppressed the TNF-induced NF-κB activation in a dose- and time-dependent manner. Suppression correlated with PTK activity, since among the structural analogues of genistein, only an active inhibitor of PTK, quercetin blocked TNF-induced NF-κB activation and not daidzein, an inactive inhibitor. Inhibition of NF-κB activation was not limited to myeloid cells, as it was observed with T cells and epithelial cells. Both the PTK inhibitors blocked the degradation of IκBα, the inhibitory subunit of NF-κB, and the consequent translocation of the p65 subunit without any significant effect on p50 or on c-Rel. The PTK inhibitors did not interfere with NF-κB binding to DNA. The NF-κB-dependent CAT reporter gene expression in transient transfection assays was also suppressed by the PTK inhibitors. Both PTK inhibitors abolished TNF-induced activation of N-terminal c-Jun kinase and mitogen-activated protein kinase kinase. Overall, our results suggest that a genistein- and erbstatin-sensitive PTK is involved in the pathway leading to NF-κB activation and gene expression by TNF and thus could be used as a target for development of antiinflammatory drugs.
来氟米特控制 MRL/MpJ-lpr/lpr 小鼠淋巴增殖和自身免疫性疾病的体内机制。
DOI：
--
发表时间：
1997
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Xu,X;Blinder,L;Shen,J;Gong,H;Finnegan,A;Williams,JW;Chong,AS
通讯作者：
Chong,AS
T 细胞中 v-src 的表达与 NF-kappa B 的核表达相关。
DOI：
--
发表时间：
1994
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Eicher,DM;Tan,TH;Rice,NR;O'Shea,JJ;Kennedy,IC
通讯作者：
Kennedy,IC
DOI：
10.1073/pnas.1416656112
发表时间：
2015-02-10
影响因子：
11.1
作者：
Batuello, Christopher N.;Hauck, Paula M.;Mayo, Lindsey D.
通讯作者：
Mayo, Lindsey D.