Effects of transcription factor activator protein-1 on interleukin-8 expression and enteritis in response to Clostridium difficile toxin Aopen access
- Authors
- Lee, Jin Young; Park, Hye Ri; Oh, Yu Kyoung; Kim, Yeong Jeon; Youn, Jeehee; Han, Joong Soo; Kim, Jung Mogg
- Issue Date
- Dec-2007
- Publisher
- SPRINGER
- Keywords
- activator protein-1; Clostridium difficile toxin A; interleukin-8; epithelial cells; mitogen-activated protein kinase
- Citation
- JOURNAL OF MOLECULAR MEDICINE-JMM, v.85, no.12, pp.1393 - 1404
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MOLECULAR MEDICINE-JMM
- Volume
- 85
- Number
- 12
- Start Page
- 1393
- End Page
- 1404
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/179257
- DOI
- 10.1007/s00109-007-0237-7
- ISSN
- 0946-2716
- 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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