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

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...

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Bibliographic Details
Published in:	Journal of leukocyte biology Vol. 79; no. 2; pp. 397 - 407
Main Authors:	Cherla, Rama P., Lee, Sang‐Yun, Mees, Pieter L., Tesh, Vernon L.
Format:	Journal Article
Language:	English
Published:	United States Society for Leukocyte Biology 01-02-2006
Subjects:	Aniline Compounds - pharmacology Anisomycin - pharmacology Anthracenes - pharmacology Cell Line, Tumor Cytokines - biosynthesis Cytokines - drug effects Dose-Response Relationship, Drug Eukaryotic Initiation Factor-4E - drug effects Eukaryotic Initiation Factor-4E - immunology Flavonoids - pharmacology Humans Imidazoles - pharmacology interleukin‐1β interleukin‐8 Lipopolysaccharides - antagonists & inhibitors Lipopolysaccharides - pharmacology Macrophages - drug effects Macrophages - immunology MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - immunology Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - immunology Phosphorylation Purines - pharmacology Pyridines - pharmacology ribotoxic stress response RNA, Messenger - drug effects RNA, Messenger - immunology Shiga Toxin 1 - antagonists & inhibitors Shiga Toxin 1 - pharmacology Time Factors
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Summary:	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 Stx1 + 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)‐1β 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0741-5400 1938-3673
DOI:	10.1189/jlb.0605313