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

J Mol Med (Berl). 2007 Dec;85(12):1393-404. doi: 10.1007/s00109-007-0237-7. Epub 2007 Jul 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / toxicity*
  • Colon / drug effects*
  • Colon / enzymology
  • Colon / metabolism
  • Colon / pathology
  • Dimerization
  • Disease Models, Animal
  • Enterotoxins / toxicity*
  • Enzyme Activation
  • Epithelial Cells / drug effects*
  • Epithelial Cells / enzymology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Genes, ras
  • HT29 Cells
  • Humans
  • Ileitis / chemically induced
  • Ileitis / enzymology
  • Ileitis / metabolism*
  • Ileitis / pathology
  • Ileitis / prevention & control
  • Imidazoles / pharmacology
  • Imidazoles / 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
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Time Factors
  • Transcription Factor AP-1 / metabolism*
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 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