Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia.
Targeted gene disruption or overexpression of 12/15-lipoxygenase in mice on the genetic background of apolipoprotein E or low density lipoprotein-receptor (LDL-R) deficiency has implicated 12/15-lipoxygenase in atherogenesis. The data support indirectly a role for 12/15-lipoxygenase in the oxidative modification of low density lipoprotein. In this study we set out to explore other potential mechanisms for 12/15-lipoxygenase in atherosclerosis using apolipoprotein B mRNA editing catalytic polypeptide-1/LDL-R double-deficient mice, a model highly related to the human condition of familial hypercholesterolemia. 12/15-Lipoxygenase deficiency in this strain led to approximately 50% decrease in aortic lesions in male and female mice at 8 months on a chow diet in the absence of cholesterol differences. While studying 12/15-lipoxygenase-deficient macrophages in culture, we discovered a remarkable selective defect (75-90% decrease) in interleukin-12 production but not in tumor necrosis factor-alpha or nitric oxide release, in response to lipopolysaccharide in the presence or absence of interferon-gamma priming. The lipopolysaccharide/interferon-gamma response was associated with a 33-50% decrease in nuclear interferon consensus sequence-binding protein, which is consistent with interferon consensus sequence-binding protein containing protein complex-dependent regulation of the interleukin-12 p40 gene. The decrease in interleukin-12 production was recapitulated in vivo in mouse aortas of the triple knockout group and was reflected in a marked decrease in interferon-gamma expression. The data provide support for a novel mechanism linking the 12/15-lipoxygenase pathway to a known immunomodulatory Th1 cytokine in atherogenesis.
Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Lei
L
Zhao
Carolyn A
CA
Cuff
Erin
E
Moss
Ulrike
U
Wille
Tillmann
T
Cyrus
Eric A
EA
Klein
Domenico
D
Praticò
Daniel J
DJ
Rader
Christopher A
CA
Hunter
Ellen
E
Puré
Colin D
CD
Funk
D000071479:APOBEC-1 Deaminase; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000502:physiology*; D001161:Arteriosclerosis / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D003564:Cytidine Deaminase / Q000235:genetics; D004195:Disease Models, Animal; D006938:Hyperlipoproteinemia Type II / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018664:Interleukin-12 / Q000096:biosynthesis*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics
D011973:Receptors, LDL; D018664:Interleukin-12; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase