EGFR kinase activity is required for TLR4 signaling and the septic shock response
EGFR kinase activity is required for TLR4 signaling and the septic shock response
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DOI：
10.15252/embr.201540337
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发表时间：
2015-11-01
期刊：
影响因子：
7.7
通讯作者：
Sen, Ganes C.
中科院分区：
文献类型：
--
作者：
Chattopadhyay, Saurabh;Veleeparambil, Manoj;Sen, Ganes C.
哺乳动物Toll样受体（TLR）识别微生物产物并引发保护受感染宿主免受疾病的瞬时免疫应答。TLR4是一种细胞内信号转导因子，它通过胞浆和胞内体膜信号转导，被细菌脂多糖（LPS）激活，并诱导多种细胞因子基因的表达，这些基因的表达延长可导致小鼠感染性休克。我们在这里报告，一些TLR4诱导的基因在骨髓细胞的表达需要表皮生长因子受体（EGFR）的蛋白激酶活性。EGFR抑制对TLR4诱导的应答的影响因靶基因而异。干扰素-（IFN-）和IFN-诱导基因的诱导被强烈抑制，而TNF-诱导被增强。抑制作用对IFN-调节因子（IRF）驱动的基因具有特异性，因为EGFR是IRF激活所必需的，TLRas下游是IRF共激活因子-连环蛋白，通过PI3激酶/AKT途径。给小鼠施用EGFR抑制剂通过选择性阻断TLR 4信号传导的IFN分支来保护它们免于LPS诱导的败血性休克和死亡。这些结果证明了EGFR对TLR4信号传导的选择性调节，并突出了EGFR抑制剂治疗脓毒性休克综合征的潜在用途。
Mammalian Toll-like receptors (TLR) recognize microbial products and elicit transient immune responses that protect the infected host from disease. TLR4which signals from both plasma and endosomal membranesis activated by bacterial lipopolysaccharides (LPS) and induces many cytokine genes, the prolonged expression of which causes septic shock in mice. We report here that the expression of some TLR4-induced genes in myeloid cells requires the protein kinase activity of the epidermal growth factor receptor (EGFR). EGFR inhibition affects TLR4-induced responses differently depending on the target gene. The induction of interferon- (IFN-) and IFN-inducible genes is strongly inhibited, whereas TNF- induction is enhanced. Inhibition is specific to the IFN-regulatory factor (IRF)-driven genes because EGFR is required for IRF activation downstream of TLRas is IRF co-activator -cateninthrough the PI3 kinase/AKT pathway. Administration of an EGFR inhibitor to mice protects them from LPS-induced septic shock and death by selectively blocking the IFN branch of TLR4 signaling. These results demonstrate a selective regulation of TLR4 signaling by EGFR and highlight the potential use of EGFR inhibitors to treat septic shock syndrome.