Shiga toxin 1-induced cytokine production is mediated by MAP kinase pathways and translation initiation factor eIF4E in the macrophage-like THP-1 cell line
Shiga toxin 1-induced cytokine production is mediated by MAP kinase pathways and translation initiation factor eIF4E in the macrophage-like THP-1 cell line
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DOI：
10.1189/jlb.0605313
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发表时间：
2006-02-01
影响因子：
5.5
通讯作者：
Tesh, Vernon L.
中科院分区：
文献类型：
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作者：
Cherla, Rama P.;Lee, Sang-Yun;Tesh, Vernon L.
志贺毒素(Stxs)与糖脂受体球三糖神经酰胺结合后，逆行转运到核糖体，裂解28S rRNA，抑制蛋白质合成。STXs可诱导某些细胞类型的核毒性应激反应以及细胞因子和趋化因子的表达。面对毒素介导的蛋白质合成抑制，细胞因子表达所需的信号机制尚未得到很好的描述。STXS可能通过多种机制调节细胞因子的表达，包括增加基因转录、mRNA转录稳定和/或提高翻译起始效率。我们发现，用纯化的STX1处理分化的THP-1细胞后，c-jun氨基末端激酶(JNK)和p38丝裂原活化蛋白激酶(MAPK)级联通路的激活时间延长，而脂多糖(LPS)迅速触发JNK和p38的瞬时激活和细胞外信号调节激酶通路的延长激活。STX1+脂多糖联合作用可延长p38MAPK的激活。STX1使真核细胞翻译起始因子4E(EIF4E)的活性在4~6h内增加4.3倍，在1h内分别增加7.8倍和11倍，eIF4E的激活需要STX1的酶活性，并由另一种核毒应激诱导剂山奈霉素介导。MAPK抑制剂或MAPK相互作用激酶1(Mnk1)特异性抑制剂的组合可阻断所有刺激剂对eIF4E的激活。Mnk1抑制可阻断STX1处理细胞中检测到的总蛋白合成的短暂增加，但不能阻止长期的蛋白质合成抑制。MAPK抑制剂或Mnk1抑制剂可阻断IL-1β和IL-8的产生或释放73-96%。这些数据表明，Stxs可能部分地通过激活MAPK级联、激活Mnk1和磷酸化eIF4E来调节细胞因子的表达。J.Leukoc。比奥尔。79：397-407；2006。
Upon binding to the glycolipid receptor globotriaosylceramide, Shiga toxins (Stxs) undergo retrograde transport to reach ribosomes, cleave 28S rRNA, and inhibit protein synthesis. Stxs induce the ribotoxic stress response and cytokine and chemokine expression in some cell types. Signaling mechanisms necessary for cytokine expression in the face of toxin-mediated protein synthesis inhibition are not well characterized. Stxs may regulate cytokine expression via multiple mechanisms involving increased gene transcription, mRNA transcript stabilization, and/or increased translation initiation efficiency. We show that treatment of differentiated THP-1 cells with purified Stx1 resulted in prolonged activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) cascades, and lipopolysaccharides (LPS) rapidly triggered transient activation of JNK and p38 and prolonged activation of extracellular signal-regulated kinase cascades. Simultaneous treatment with Stx1 + LPS mediated prolonged p38 MAPK activation. Stx1 increased eukaryotic translation initiation factor 4E (eIF4E) activation by 4.3-fold within 4 - 6 h, and LPS or Stxl + LPS treatment increased eIF4E activation by 7.8- and 11-fold, respectively, within 1 h. eIF4E activation required Stx1 enzymatic activity and was mediated by anisomycin, another ribotoxic, stress inducer. A combination of MAPK inhibitors or a MAPK-interacting kinase 1 (Mnk1)-specific inhibitor blocked eIF4E activation by all stimulants. Mnk1 inhibition blocked the transient increase in total protein synthesis detected in Stx1-treated cells but failed to block long-term protein synthesis inhibition. The MAPK inhibitors or Mnk1 inhibitor blocked soluble interleukin (IL)-1 beta and IL-8 production or release by 73-96%. These data suggest that Stxs may regulate cytokine expression in part through activation of MAPK cascades, activation of Mnk1, and phosphorylation of eIF4E. J. Leukoc. Biol. 79: 397-407; 2006.