Deficiency of 5-lipoxygenase abolishes sex-related survival differences inMRL-lpr/lpr mice

Leukotrienes, the 5-lipoxygenase (5LO) products of arachidonic acid metabol ism, have many proinflammatory actions that have been implicated in the pat hogenesis of a variety of inflammatory diseases. To investigate the role of LTs in autoimmune disease, we generated an MRL-lpr/lpr mouse line,vith a t argeted disruption of the 5lo gene. MRL-lpr/lpr mice spontaneously develop autoimmune disease that has many features resembling human systemic lupus e rythematosus, including sex-related survival differences; female MRL-lpr/lp r mice experience significant early mortality compared with males. Unexpect edly, we found that mortality was accelerated in male 5LO-deficient MRL-lpr /lpr mice compared with male wild-type MRL-lpr/lpr animals. In contrast, th e 510 mutation had no effect on survival in females. Mortality was also acc elerated in male MRL-lpr/lpr mice that were treated chronically with a phar macological inhibitor of LT synthesis. Furthermore, LT-dependent inflammato ry responses are enhanced in male MRL-lpr/lpr mice compared with females, a nd the 510 mutation has greater impact on these responses in males. Because immune complex-mediated glomerulonephritis is the major cause of death in MRL-lpr/lpr mice and has been related to arachidonic acid metabolites, we a lso assessed kidney function and histopathology, In male MRL-lpr/lpr mice, renal plasma flow was significantly reduced in the 5lo(-/-) compared with t he 5lo(+/+) group, although there were no differences in the severity of re nal histopathology, lymphoid hyperplasia, or arthritis between the groups. These findings suggest that the presence of a functional 510 gene confers a survival advantage on male MRL-lpr/lpr mice and that, when 5LO function is inhibited, either genetically or pharmacologically, this advantage is abol ished.