Effects of transcription factor activator protein-1 on interleukin-8 expression and enteritis in response to Clostridium difficile toxin A.
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.
Lee
Jin Young
JY
Department of Microbiology and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, 133-791, South Korea.
Park
Hye Ri
HR
Oh
Yu-Kyoung
YK
Kim
Yeong-Jeon
YJ
Youn
Jeehee
J
Han
Joong-Soo
JS
Kim
Jung Mogg
JM
D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019281:Dimerization; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000633:toxicity*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011905:Genes, ras; D019073:HT29 Cells; D006801:Humans; D007079:Ileitis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D016209:Interleukin-8 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001427:Bacterial Toxins; D004768:Enterotoxins; D007093:Imidazoles; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D018808:Transcription Factor AP-1; C041348:tcdA protein, Clostridium difficile; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580