Regulation of Cytokine and Chemokine Expression by the Ribotoxic Stress Response Elicited by Shiga Toxin Type 1 in Human Macrophage-Like THP-1 Cells
Regulation of Cytokine and Chemokine Expression by the Ribotoxic Stress Response Elicited by Shiga Toxin Type 1 in Human Macrophage-Like THP-1 Cells
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DOI：
10.1128/iai.06025-11
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发表时间：
2012-06-01
影响因子：
3.1
通讯作者：
Tesh, Vernon L.
中科院分区：
文献类型：
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作者：
Leyva-Illades, Dinorah;Cherla, Rama P.;Tesh, Vernon L.
志贺毒素(Stxs)是由肠道病原菌志贺氏菌1型和产志贺菌毒素的大肠杆菌(STEC)产生的细胞毒素。STX与膜糖脂受体结合，进入细胞，进行逆行转运，最终到达胞浆，在那里，毒素通过从真核细胞核糖体的28S rRNA组分中提纯单个腺嘌呤残基来发挥其蛋白质合成抑制活性。去嘌呤反应激活核毒应激反应，导致在人上皮细胞、内皮细胞和髓系细胞中通过丝裂原活化蛋白激酶(MAPK)通路(Jun N末端蛋白激酶[JNK]、p38和细胞外信号调节激酶[ERK])进行信号传递。我们以前发现，用STXS处理人巨噬细胞样THP-1细胞后，细胞因子和趋化因子的表达增加。在本研究中，我们发现，在STX1存在的情况下，使用药物抑制剂单独灭活ERK、JNK和p38 MAPK会导致细胞因子肿瘤坏死因子α和白细胞介素1β(IL-1β)以及趋化因子IL-8、生长调节蛋白-β、巨噬细胞炎症蛋白-1α(MIP-1α)和MIP-1β的不同调节。暴露于Sw的THP-1细胞上调哺乳动物细胞中选择性双特异性磷酸酶(DUSPs)的表达，DUSPs是一种使MAPKs去磷酸化和失活的酶。在这项研究中，我们证实了STX1处理的THP-1细胞产生了DUSP1蛋白。雷公藤甲素对DUSP1的抑制表明，ERK和p38的磷酸化受DUSP1的调节，而JNK的磷酸化不受DUSP1的调节。抑制p38MAPK信号转导阻断了STX1诱导DUSP1mRNA表达的能力，提示SECs可能激活了一个自身调节的信号环。因此，Stxs似乎能够激发信号，激活和抑制人巨噬细胞样细胞中细胞因子/趋化因子产生增加的信号。
Shiga toxins (Stxs) are cytotoxins produced by the enteric pathogens Shigella dysenteriae serotype 1 and Shiga toxin-producing Escherichia coli (STEC). Stxs bind to a membrane glycolipid receptor, enter cells, and undergo retrograde transport to ultimately reach the cytosol, where the toxins exert their protein synthesis-inhibitory activity by depurination of a single adenine residue from the 28S rRNA component of eukaryotic ribosomes. The depurination reaction activates the ribotoxic stress response, leading to signaling via the mitogen-activated protein kinase (MAPK) pathways (Jun N-terminal protein kinase [JNK], p38, and extracellular signal-regulated kinase [ERK]) in human epithelial, endothelial, and myeloid cells. We previously showed that treatment of human macrophage-like THP-1 cells with Stxs resulted in increased cytokine and chemokine expression. In the present study, we show that individual inactivation of ERK, JNK, and p38 MAPKs using pharmacological inhibitors in the presence of Stx1 resulted in differential regulation of the cytokines tumor necrosis factor alpha and interleukin-1 beta (IL-1 beta) and chemokines IL-8, growth-regulated protein-beta, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta. THP-1 cells exposed to SW upregulate the expression of select dual-specificity phosphatases (DUSPs), enzymes that dephosphorylate and inactivate MAPKs in mammalian cells. In this study, we confirmed DUSP1 protein production by THP-1 cells treated with Stx1. DUSP1 inhibition by triptolide showed that ERK and p38 phosphorylation is regulated by DUSP1, while JNK phosphorylation is not. Inhibition of p38 MAPK signaling blocked the ability of Stx1 to induce DUSP1 mRNA expression, suggesting that an autoregulatory signaling loop may be activated by Secs. Thus, Stxs appear to be capable of eliciting signals which both activate and deactivate signaling for increased cytokine/chemokine production in human macrophage-like cells.