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Am J Physiol Cell Physiol (September 4, 2002). doi:10.1152/ajpcell.00271.2002
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Articles in PresS, published online ahead of print September 4, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00271.2002
Submitted on June 14, 2002
Accepted on August 19, 2002

TNF-{alpha} Induced Endothelial Cell Adhesion Molecule Expression Is Cytochrome P450 Monooxygenase Dependent

Makoto Sasaki1, D Ostanin1, J W Elrod1, T Oshima1, P Jordan1, M Itoh2, T Joh2, A Minagar1, and J S Alexander1*

1 Physiology, LSU Health Sciences Center, Shreveport, LA, USA
2 First Department of Internal Medicine, Nagoya City University Medical School, Nagoya, Japan, Japan

* To whom correspondence should be addressed. E-mail: jalexa{at}lsuhsc.edu.

It is well accepted that cytokine induced gene expression in inflammation is oxidant-mediated, however, the intracellular sources of signal oxidants remain controversial. In inflammatory bowel disease pro-inflammatory cytokines, like TNF-{alpha}, trigger gene expression of endothelial adhesion molecules including mucosal addressin cell adhesion molecule-1 (MAdCAM-1). MAdCAM plays an essential role in gut inflammation by governing the infiltration of leukocytes into the intestine. Several groups suggest that endothelial derived NADPH oxidase produces signaling oxidants that control the expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1). In addition to NADPH oxidase, cytochrome P450 (CYP450) monooxygenases have also been shown to trigger cytokine responses. We found that in high endothelial venular cells (SVEC4-10), multiple inhibitors of CYPP450 monooxygenases (SKF525a, ketoconazole, troleandomycin, itraconazole) attenuated TNF-{alpha} induction of MAdCAM-1, while NADPH oxidase inhibition (PR-39) did not. Conversely, E-selectin, ICAM-1, and VCAM-1 induction requires both NADPH oxidase and CYP450 derived oxidants. We show here that MAdCAM-1 induction may depend exclusively on CYP450 derived oxidants, suggesting that CYP450 blockers might represent a possible novel therapeutic treatment for human IBD.




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