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INFLAMMATION/IMMUNITY/MEDIATORS

5-Lipoxygenase-derived lipid mediators are not required for the development of NSAID-induced inflammatory bowel disease in IL-10^–/– mice

¹Department of Internal Medicine, ²Department of Pediatrics, University of Iowa College of Medicine, Iowa City, Iowa

Submitted 21 May 2007 ; accepted in final form 29 November 2007

Leukotrienes are potent lipid mediators derived from the metabolism of arachidonic acid by the enzyme 5-lipoxygenase (5-LO). Elevated levels of the proinflammatory leukotriene LTB₄ have been found in preclinical models of inflammatory bowel disease (IBD) as well as in colon tissue from individuals with IBD. We therefore determined the extent to which absence of 5-LO-derived lipid mediators would alter the colitis in IL-10^–/– mice, a model of human IBD. IL-10^–/–/5-LO^–/– mice were generated and were healthy. Absence of 5-LO did not alter the development of spontaneous colitis in IL-10-deficient mice. We then evaluated the extent to which absence of 5-LO would alter the development of NSAID-induced colitis in IL-10^–/– mice. Absence of 5-LO did not delay the onset or alter the severity of inflammation in NSAID-treated IL-10^–/– mice. At an early time point, 3 days after NSAID treatment was initiated, a qualitative increase in the number of dendritic cells and CD4⁺ T cells was noted in the colons of IL-10^–/–/5-LO^–/–; however, this difference was no longer present after 14 days of NSAID treatment. Absence of 5-LO did not alter the degree of neutrophil infiltration into the in this model. Absence of 5-LO does not alter the development of IFN- producing Th1-type CD4⁺ T cells or IL-17 producing CD4⁺ T cells. Absence of 5-LO-derived mediators did not alter the expression of the adhesion molecules ICAM-1 and P-selectin. Development of colitis in IL-10^–/– mice was associated with increased levels of the 5-LO-derived anti-inflammatory lipoxin LXA₄. These studies demonstrate that 5-LO-derived leukotrienes are not required for the development or maintenance of spontaneous or NSAID-induced colonic inflammation in IL-10^–/– mice.

cytokines; leukotriene; lipid mediators; inflammation