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 LTB(4) 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-gamma 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 LXA(4). 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.