5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration

Leukotrienes play a part in inflammatory response. The unique role of the enzyme 5-lipoxygenase (5-LO) in the production of leukotrienes makes it as therapeutic target for inflammatory conditions like inflammatory bowel disease (IBD). In the present study, by comparing the responses in wild-type mice (5-LOWT) and mice lacking the 5-lipoxygenase (5-LOKO), we investigated the role played by this enzyme in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid ( DNBS). When compared to DNBS-treated 5-LOWT mice, DNBS-treated 5-LOKO mice experienced a reduced rate of the extent and severity of the histological signs of colon injury. After administration of DNBS 5-LOWT mice showed hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon. Neutrophil infiltration was associated with the expression of ICAM-1, VCAM-1, P-selectin, E-selectin that were mainly localized around vessels. Absence of a functional 5-LO resulted in a significant reduction of all the above-described parameters. In particular, we have observed a significant reduction of: (i) the degree of colon injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in staining ( immunohistochemistry) for ICAM-1, VCAM-1, P-selectin, E-selectin caused by DNBS in the colon. Similarly, the treatment of 5-LOWT with zileuton (50 mg/kg per os twice a day) resulted in a significant reduction of all the above-described parameters. In addition, in in vitro study a significantly reduced chemotactic response to IL-8 was observed in peripheral blood leukocytes from 5-LOKO in comparison to 5-LOWT polymorphonuclear leukocyte. Similar results were obtained when we analyzed the chemotactic response of 5-LOWT cell incubated for 15 min with zileuton (50 mu g/ml). Taken together, our results clearly demonstrate that 5-LO modulates neutrophil infiltration in experimental colitis through the expression of adhesion molecules.