Mitogen-activated protein kinase and activator protein-1 dependent signals are essential for Bacteroides fragilis enterotoxin-induced enteritis

Eur J Immunol. 2005 Sep;35(9):2648-57. doi: 10.1002/eji.200526321.


The approximately 20-kDa heat-labile toxin produced by enterotoxigenic Bacteroides fragilis is known to be associated with the development of enteritis. However, the molecular mechanism involved is not yet fully understood. In this study, we assessed whether B. fragilis enterotoxin (BFT)-induced enteritis is related to mitogen-activated protein kinase (MAPK) signaling pathways. In human colon epithelial cells, BFT activated three major MAPK cascades. The activation of p38 was sustained for a relatively long period, while the stimulation of extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) was transient. BFT stimulation also activated AP-1 signals composed of c-Jun/c-Fos heterodimers. The p38 inhibitor SB203580 and the ERK inhibitor U0126 reduced not only AP-1 activity, but also decreased IL-8 and MCP-1 expression. In addition, the overexpression of superrepressors for c-Jun and Ras induced by BFT stimulation decreased the levels of IL-8 and MCP-1 production. Furthermore, SB203580 prevented BFT-induced colitis in the mouse ileum, as evidenced by significant decreases in villous destruction, neutrophil infiltration, and mucosal congestion. These results suggest that a pathway, including Ras, MAPK, and subsequent AP-1 activation, is required for IL-8 and MCP-1 expression in intestinal epithelial cells exposed to BFT, and can be involved in the development of enteritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Toxins / immunology*
  • Bacteroides Infections / immunology*
  • Bacteroides Infections / microbiology
  • Bacteroides fragilis / enzymology
  • Butadienes / pharmacology
  • Chemokine CCL2 / biosynthesis
  • Chemokine CCL2 / immunology
  • Colon / enzymology
  • Colon / immunology
  • Colon / microbiology
  • Colon / pathology
  • Down-Regulation
  • Enteritis / enzymology*
  • Enteritis / immunology
  • Enteritis / microbiology
  • Enteritis / prevention & control
  • HL-60 Cells
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / immunology
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • MAP Kinase Signaling System / immunology*
  • Metalloendopeptidases / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / immunology
  • Nitriles / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology
  • Specific Pathogen-Free Organisms
  • Transcription Factor AP-1 / immunology*


  • Bacterial Toxins
  • Butadienes
  • Chemokine CCL2
  • Imidazoles
  • Interleukin-8
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyridines
  • Transcription Factor AP-1
  • U 0126
  • Mitogen-Activated Protein Kinases
  • Bacteroides fragilis toxin
  • Metalloendopeptidases
  • SB 203580