Deficiency of 5-lipoxygenase abolishes sex-related survival differences in MRL-lpr/lpr mice.
Leukotrienes, the 5-lipoxygenase (5LO) products of arachidonic acid metabolism, have many proinflammatory actions that have been implicated in the pathogenesis of a variety of inflammatory diseases. To investigate the role of LTs in autoimmune disease, we generated an MRL-lpr/lpr mouse line with a targeted disruption of the 5lo gene. MRL-lpr/lpr mice spontaneously develop autoimmune disease that has many features resembling human systemic lupus erythematosus, including sex-related survival differences; female MRL-lpr/lpr mice experience significant early mortality compared with males. Unexpectedly, 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, the 5lo mutation had no effect on survival in females. Mortality was also accelerated in male MRL-lpr/lpr mice that were treated chronically with a pharmacological inhibitor of LT synthesis. Furthermore, LT-dependent inflammatory responses are enhanced in male MRL-lpr/lpr mice compared with females, and the 5lo 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 also assessed kidney function and histopathology. In male MRL-lpr/lpr mice, renal plasma flow was significantly reduced in the 5lo-/- compared with the 5lo+/+ group, although there were no differences in the severity of renal histopathology, lymphoid hyperplasia, or arthritis between the groups. These findings suggest that the presence of a functional 5lo 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 abolished.
Goulet
J L
JL
Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC 27705, USA.
Griffiths
R C
RC
Ruiz
P
P
Spurney
R F
RF
Pisetsky
D S
DS
Koller
B H
BH
Coffman
T M
TM
D000208:Acute Disease; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000235:genetics*; D001168:Arthritis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis; D005260:Female; D005919:Glomerular Filtration Rate / Q000235:genetics / Q000276:immunology; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000401:mortality*; D008232:Lymphoproliferative Disorders / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D012079:Renal Circulation / Q000235:genetics / Q000276:immunology; D012737:Sex Factors; D002722:Chlorobenzenes
D001094:Arachidonate 5-Lipoxygenase; D001323:Autoantibodies; D007211:Indoles; D016859:Lipoxygenase Inhibitors; C060893:MK-886; D002722:Chlorobenzenes