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Effects of transcription factor activator protein-1 on interleukin-8 expression and enteritis in response to Clostridium difficile toxin A.

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.
AuthorsJin Young Lee, Hye Ri Park, Yu-Kyoung Oh, Yeong-Jeon Kim, Jeehee Youn, Joong-Soo Han, Jung Mogg Kim
JournalJournal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 85 Issue 12 Pg. 1393-404 (Dec 2007) ISSN: 0946-2716 [Print] Germany
PMID17639289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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