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Am J Physiol Cell Physiol 284: C422-C428, 2003. First published September 4, 2002; doi:10.1152/ajpcell.00271.2002
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Vol. 284, Issue 2, C422-C428, February 2003

TNF-alpha -induced endothelial cell adhesion molecule expression is cytochrome P-450 monooxygenase dependent

Makoto Sasaki1, D. Ostanin1, J. W. Elrod1, T. Oshima4, P. Jordan2, M. Itoh4, T. Joh4, A. Minagar3, and J. S. Alexander1

Departments of 1 Molecular and Cellular Physiology, 2 Gastroenterology, and 3 Neurology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932; and 4 First Department of Internal Medicine, Nagoya City University Medical School, Nagoya, Japan

It is strongly suspected that cytokine-induced gene expression in inflammation is oxidant mediated; however, the intracellular sources of signaling oxidants remain controversial. In inflammatory bowel disease (IBD) proinflammatory cytokines, such as TNF-alpha , trigger gene expression of endothelial adhesion molecules including mucosal addressin cell adhesion molecule-1 (MAdCAM-1). MAdCAM-1 plays an essential role in gut inflammation by governing the infiltration of leukocytes into the intestine. Several groups suggest that endothelial-derived reduced NADP (NADPH) oxidase produces signaling oxidants that control the expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1). In addition to NADPH oxidase, cytochrome P-450 (CYP450) monooxygenases have also been shown to trigger cytokine responses. We found that in high endothelial venular cells (SVEC4-10), multiple inhibitors of CYP450 monooxygenases (SKF-525a, ketoconazole, troleandomycin, itraconazole) attenuated TNF-alpha induction of MAdCAM-1, whereas 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.

cytochrome P-450 monooxygenase; reduced nicotinamide adenine dinucleotide phosphate oxygenase; mucosal addressin cell adhesion molecule-1; inflammatory bowel disease; endothelial cell adhesion molecules


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