p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis
| Autor: | J. Thomas Lamont, Ciaran P. Kelly, Michel Warny, Ignazio Castagliuolo, Jeff K. Zacks, Andrew C. Keates, Samer Aboudola, Amir A. Qamar, C Pothoulakis, Sarah Keates |
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| Rok vydání: | 2000 |
| Předmět: |
rho GTP-Binding Proteins
Glycosylation MAP Kinase Signaling System Neutrophils Mitogen-Activated Protein Kinase 3 p38 mitogen-activated protein kinases Bacterial Toxins Clostridium difficile toxin A medicine.disease_cause p38 Mitogen-Activated Protein Kinases Monocytes Article Cell Line Enterotoxins Mice medicine Animals Mitogen-Activated Protein Kinase 8 Enterocolitis Pseudomembranous Mitogen-Activated Protein Kinase 1 biology Clostridioides difficile Toxin Kinase MEK inhibitor Monocyte Interleukin-8 General Medicine Molecular biology Enteritis Enzyme Activation medicine.anatomical_structure Gene Expression Regulation Neutrophil Infiltration Mitogen-activated protein kinase biology.protein Mitogen-Activated Protein Kinases |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 0021-9738 |
| Popis: | Clostridium difficile toxin A causes acute neutrophil infiltration and intestinal mucosal injury. In cultured cells, toxin A inactivates Rho proteins by monoglucosylation. In monocytes, toxin A induces IL-8 production and necrosis by unknown mechanisms. We investigated the role of mitogen-activated protein (MAP) kinases in these events. In THP-1 monocytic cells, toxin A activated the 3 main MAP kinase cascades within 1 to 2 minutes. Activation of p38 was sustained, whereas stimulation of extracellular signal-regulated kinases and c-Jun NH(2)-terminal kinase was transient. Rho glucosylation became evident after 15 minutes. IL-8 gene expression was reduced by 70% by the MEK inhibitor PD98059 and abrogated by the p38 inhibitor SB203580 or by overexpression of dominant-negative mutants of the p38-activating kinases MKK3 and MKK6. SB203580 also blocked monocyte necrosis and IL-1beta release caused by toxin A but not by other toxins. Finally, in mouse ileum, SB203580 prevented toxin A-induced neutrophil recruitment by 92% and villous destruction by 90%. Thus, in monocytes exposed to toxin A, MAP kinase activation appears to precede Rho glucosylation and is required for IL-8 transcription and cell necrosis. p38 MAP kinase also mediates intestinal inflammation and mucosal damage induced by toxin A. |
| Databáze: | OpenAIRE |
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