Abstract |
Clostridium difficile toxin A causes acute colitis associated with intense infiltration of neutrophils. Although C. difficile toxin A is known to induce nuclear factor-kappaB-mediated chemokine expression in intestinal epithelial cells, little is known about its effect on the regulation of activator protein-1 (AP-1) by mitogen-activated protein kinase (MAPK). In the present study, we investigated whether the MAPK and AP-1 signaling pathway is involved in interleukin (IL)-8 expression and enteric inflammation in response to stimulation with toxin A. Toxin A activated MAPK and AP-1 composed of c-Jun/c-Fos heterodimers in primary intestinal epithelial cells and HT-29 cell lines. Transfection with mutant genes for Ras, c-Jun, p38, or c-Jun N-terminal kinase (JNK) significantly inhibited C. difficile toxin A-induced activation of AP-1 and expression of IL-8 in HT-29 cell lines. Furthermore, the p38 inhibitor SB203580 attenuated toxin A-induced inflammation in vivo in the mouse ileum, evidenced by a significant decrease in neutrophil infiltration, villous destruction, and mucosal congestion. Our results suggest that the Ras/MAPK cascade acts as the upstream signaling for AP-1 activation and IL-8 expression in toxin A-stimulated intestinal epithelial cells and may be involved in the development of enteritis after infection with toxin A-producing C. difficile.
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Authors | Jin Young Lee, Hye Ri Park, Yu-Kyoung Oh, Yeong-Jeon Kim, Jeehee Youn, Joong-Soo Han, Jung Mogg Kim |
Journal | Journal of molecular medicine (Berlin, Germany)
(J Mol Med (Berl))
Vol. 85
Issue 12
Pg. 1393-404
(Dec 2007)
ISSN: 0946-2716 [Print] Germany |
PMID | 17639289
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Bacterial Toxins
- Enterotoxins
- Imidazoles
- Interleukin-8
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins c-fos
- Proto-Oncogene Proteins c-jun
- Pyridines
- Transcription Factor AP-1
- tcdA protein, Clostridium difficile
- JNK Mitogen-Activated Protein Kinases
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinases
- p38 Mitogen-Activated Protein Kinases
- SB 203580
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Topics |
- Animals
- Bacterial Toxins
(toxicity)
- Colon
(drug effects, enzymology, metabolism, pathology)
- Dimerization
- Disease Models, Animal
- Enterotoxins
(toxicity)
- Enzyme Activation
- Epithelial Cells
(drug effects, enzymology, metabolism, pathology)
- Genes, ras
- HT29 Cells
- Humans
- Ileitis
(chemically induced, enzymology, metabolism, pathology, prevention & control)
- Imidazoles
(pharmacology, therapeutic use)
- Interleukin-8
(metabolism)
- JNK Mitogen-Activated Protein Kinases
(metabolism)
- MAP Kinase Signaling System
(drug effects)
- Mice
- Mice, Inbred C57BL
- Mitogen-Activated Protein Kinase 1
(metabolism)
- Mitogen-Activated Protein Kinase 3
(metabolism)
- Mitogen-Activated Protein Kinases
(antagonists & inhibitors, genetics, metabolism)
- Mutation
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Proto-Oncogene Proteins c-fos
(metabolism)
- Proto-Oncogene Proteins c-jun
(metabolism)
- Pyridines
(pharmacology, therapeutic use)
- Time Factors
- Transcription Factor AP-1
(metabolism)
- Transfection
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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