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We have previously shown that interferon-γ (IFN-γ) is a potent enhancer of atherogenesis. Interleukin-18 (IL-18) promotes inflammatory responses through release of IFN-γ, although it can also exert direct actions on other inflammatory mediators. In this present study, we determined the effects of IL-18 on atherogenesis and the role of IFN-γ in this response. Male apolipoprotein E^−/− mice (apoe^−/−; aged 16 weeks, n=10/group) were fed a normal diet and injected intraperitoneally for 30 days with either recombinant IL-18 (30 ng/g/day) or saline. Atherosclerotic lesion size was quantified in 2 vascular beds: the ascending aorta and the aortic arch. IL-18 administration did not affect serum cholesterol concentrations or lipoprotein-cholesterol distribution; however, exogenous IL-18 administration increased lesion size 2-fold in both the ascending aorta (50 642±12 515 versus 112 399±13 227 μm², P=0.004; saline versus …