IL-6 activates serum and glucocorticoid kinase via p38α mitogen-activated protein kinase pathway
IL-6 activates serum and glucocorticoid kinase via p38α mitogen-activated protein kinase pathway
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DOI：
10.1152/ajpcell.00081.2005
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发表时间：
2005-10-01
影响因子：
5.5
通讯作者：
Patel, T
中科院分区：
文献类型：
--
作者：
Meng, FM;Yamagiwa, Y;Patel, T
白细胞介素-6（IL-6）是一种自分泌因子，参与多种人类癌症的生长，如胆道肿瘤或胆管癌。在恶性胆道上皮中，IL-6激活p38 MAPK通路，其介导显性存活信号通路。血清和糖皮质激素刺激的激酶（SGK）被认为是一种存活激酶，但其在IL-6的存活信号传导中的作用尚不清楚。IL-6刺激后，p38 MAPK活化先于SGK Ser磷酸化（78）。用p38 MAPK的药理学抑制剂SB-203580或SB-202190预处理阻断IL-6诱导的SGK在Ser 78处的磷酸化和SGK活化。p38 α的过表达增加了SGK在Ser 78的组成性磷酸化，而显性负性p38 α MAPK阻断了IL-6诱导的SGK磷酸化和核转位。有趣的是，除了刺激SGK磷酸化外，IL-6刺激和p38 α MAPK过表达均增加SGK mRNA和蛋白表达。p38 MAPK和SGK的增加发生在体内IL-6的强制表达后。此外，通过siRNA抑制SGK表达增加了化疗药物的毒性。总之，这些数据鉴定SGK作为下游激酶底物以及响应于IL-6的p38 MAPK的转录调节基因靶标，并支持SGK在人类癌症（如胆管癌）中通过IL-6的存活信号传导期间的作用。
Interleukin-6 (IL-6) has been implicated as an autocrine factor involved in growth of several human cancers, such as tumors arising from the biliary tract or cholangiocarcinoma. In malignant biliary tract epithelia, IL-6 activates the p38 MAPK pathway, which mediates a dominant survival signaling pathway. Serum and glucocorticoid-stimulated kinase (SGK) has been implicated as a survival kinase, but its role in survival signaling by IL-6 is unknown. After IL-6 stimulation, p38 MAPK activation preceded phosphorylation of SGK at Ser(78). Pretreatment with the pharmacological inhibitors of p38 MAPK SB-203580 or SB-202190 blocked IL-6-induced SGK phosphorylation at Ser78 and SGK activation. Overexpression of p38 alpha increased constitutive SGK phosphorylation at Ser78, whereas dominant negative p38 alpha MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38 alpha MAPK overexpression increased SGK mRNA and protein expression. An increase in p38 MAPK and SGK occurred following enforced expression of IL-6 in vivo. Furthermore, inhibition of SGK expression by siRNA increased toxicity due to chemotherapeutic drugs. Taken together, these data identify SGK as both a downstream kinase substrate as well as a transcriptionally regulated gene target of p38 MAPK in response to IL-6 and support a role of SGK during survival signaling by IL-6 in human cancers, such as cholangiocarcinoma.