IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E-/- mice

We have shown recently that administration of exogenous interferon-gamma (IFN-gamma) to apolipoprotein E (apoE)(-/-) mice augmented atherogenesis. In the present study, we examined whether deficiency of endogenous IFN-gamma would reduce atherosclerosis in apoE(-/-) mice. Compound-deficient mice were generated by crossing strain-matched IFN-gamma(-/-) and apoE(-/-) mice and comparing them to apoE(-/-) mice. Groups of both genders were fed either a normal or a high-fat diet. IFN-gamma deficiency did not affect serum cholesterol concentrations or lipoprotein-cholesterol distributions in any groups. IFN-gamma deficiency had no effect on serum triglyceride concentrations, except for an increase noted in males fed a normal diet. The extent of atherosclerosis was determined in tissue sections of the ascending aorta and on the surface of the aortic arch. During feeding of normal diets, IFN-gamma deficiency had no effect on the extent of atherosclerosis in female mice in either vascular bed. In contrast, in male mice fed normal diet, IFN-gamma deficiency markedly decreased lesion size in both vascular beds. During feeding of high-fat diets, IFN-gamma deficiency also had no effect on lesion size in females but profoundly decreased lesion size in the aortic root of male mice. IFN-gamma deficiency had no effect on the abundance of T lymphocytes or MHC class II-positive cells in aortic root lesions of females. By comparison, both these parameters were reduced in lesions of male mice. Therefore, IFN-gamma deficiency decreased atherogenesis, potentially by decreasing T lymphocyte presence and cell activation, without influencing serum cholesterol concentrations. However, this effect is strikingly restricted to male mice.