p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis.

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)