Abstract |
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.
|
Authors | M Warny, A C Keates, S Keates, I Castagliuolo, J K Zacks, S Aboudola, A Qamar, C Pothoulakis, J T LaMont, C P Kelly |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 105
Issue 8
Pg. 1147-56
(Apr 2000)
ISSN: 0021-9738 [Print] United States |
PMID | 10772660
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
|
Chemical References |
- Bacterial Toxins
- Enterotoxins
- Interleukin-8
- tcdA protein, Clostridium difficile
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 8
- Mitogen-Activated Protein Kinases
- p38 Mitogen-Activated Protein Kinases
- rho GTP-Binding Proteins
|
Topics |
- Animals
- Bacterial Toxins
(metabolism, pharmacology)
- Cell Line
- Clostridioides difficile
(immunology, metabolism)
- Enteritis
(enzymology, immunology, microbiology)
- Enterocolitis, Pseudomembranous
(enzymology, immunology, microbiology)
- Enterotoxins
(metabolism, pharmacology)
- Enzyme Activation
- Gene Expression Regulation
(drug effects)
- Glycosylation
- Interleukin-8
(biosynthesis, genetics)
- MAP Kinase Signaling System
- Mice
- Mitogen-Activated Protein Kinase 1
(metabolism)
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinase 8
- Mitogen-Activated Protein Kinases
(antagonists & inhibitors, immunology, metabolism)
- Monocytes
(immunology, metabolism, pathology)
- Neutrophil Infiltration
(immunology)
- Neutrophils
(immunology)
- p38 Mitogen-Activated Protein Kinases
- rho GTP-Binding Proteins
(immunology, metabolism)
|