Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases.
Endotoxin Tolerance Inhibits Lyn and c-Src Phosphorylation and Association with Toll-Like Receptor 4 but Increases Expression and Activity of Protein Phosphatases.
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DOI：
10.1159/000440838
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发表时间：
2016
影响因子：
5.3
通讯作者：
Medvedev AE
中科院分区：
文献类型：
--
作者：
Xiong Y;Murphy M;Manavalan TT;Pattabiraman G;Qiu F;Chang HH;Ho IC;Medvedev AE
内毒素耐受性通过限制败血症期间过度的“细胞因子风暴”来保护宿主，但会损害败血性休克幸存者抵抗感染的能力。它通过减弱促炎细胞因子的表达来重编程 Toll 样受体 (TLR) 4 反应，而不抑制抗炎和抗菌介质，但重编程的机制仍不清楚。在这项研究中，我们证明，在人单核细胞、THP-1 和 MonoMac-6 细胞中诱导内毒素耐受可抑制脂多糖 (LPS) 介导的 Lyn、c-Src 磷酸化及其向 TLR4 的募集，但增加总蛋白磷酸酶 (PP) 活性和蛋白酪氨酸磷酸酶 (PTP) 1B、PP2A、PTP 非受体型 (PTPN) 22 和丝裂原激活的表达蛋白激酶磷酸酶（MKP）-1。化学PP抑制剂，冈田酸，去磷酸酶和斑蝥酸，显着降低或完全消除LPS耐受性，表明磷酸酶在内毒素耐受中的重要性。 PTPN22的过表达降低了LPS介导的核因子(NF)-κB激活、p38磷酸化和CXCL8基因表达，而PTPN22消融上调了LPS诱导的p65 NF-κB和p38磷酸化以及TNF-α和pro-IL-1β mRNA的表达，表明PTPN22是TLR4信号传导的抑制剂。因此，LPS 耐受性通过抑制 Lyn 和 c-Src 磷酸化以及它们向 TLR4 的募集来干扰 TLR4 信号传导，同时增加磷酸酶活性以及 PP2A、PTPN22、PTP1B 和 MKP1 的表达。
Endotoxin tolerance protects the host by limiting excessive “cytokine storm” during sepsis, but compromises the ability to counteract infections in septic shock survivors. It reprograms Toll-like receptor (TLR) 4 responses by attenuating expression of pro-inflammatory cytokines without suppressing anti-inflammatory and antimicrobial mediators, but the mechanisms of reprogramming remain unclear. In this study, we demonstrate that induction of endotoxin tolerance in human monocytes, THP-1 and MonoMac-6 cells inhibited lipopolysaccharide (LPS)-mediated phosphorylation of Lyn, c-Src and their recruitment to TLR4 but increased total protein phosphatase (PP) activity and expression of protein tyrosine phosphatase (PTP) 1B, PP2A, PTP non-receptor type (PTPN) 22, and mitogen-activated protein kinase phosphatase (MKP)-1. Chemical PP inhibitors, okadaic acid, dephostatin and cantharidic acid, markedly decreased or completely abolished LPS tolerance, indicating the importance of phosphatases in endotoxin tolerization. Overexpression of PTPN22 decreased LPS-mediated nuclear factor (NF)-κB activation, p38 phosphorylation, and CXCL8 gene expression, while PTPN22 ablation up-regulated LPS-induced p65 NF-κB and p38 phosphorylation and expression of TNF-α and pro-IL-1β mRNA, indicating PTPN22 as an inhibitor of TLR4 signaling. Thus, LPS tolerance interferes with TLR4 signaling by inhibiting Lyn and c-Src phosphorylation, their recruitment to TLR4, while increasing phosphatase activity and expression of PP2A, PTPN22, PTP1B and MKP1.