Proatherogenic effect of interleukin-18 is exerted with high-fat diet, but not with normal diet in spontaneously hyperlipidemic mice

Aim: It has been considered that interleukin (IL)-18, a T helper 1(Th1) type cytokine, has a promoting effect on atherosclerosis development. A previous mouse study demonstrated that short-term exogenous IL-18 promoted atherosclerosis through a Th1 type immune response; however, the serum IL-18 may have increased greatly beyond its physiological range, and the effect of increased serum IL-18 on atherosclerosis development has not been investigated under different conditions of dietary fat content. The purpose of this study was to reveal the effect of increased serum IL-18 within its physiological fluctuations on atherosclerosis development under different conditions of dietary fat content. Methods: Spontaneously hyperlipidemic (SHL) mice were systemically supplied with IL-18 for 10 weeks by means of an in vivo gene transfer system with a high-fat diet containing 0.15% cholesterol or a normal diet. Results: Serum IL-18 steadily elevated within its physiological fluctuations. An atherosclerotic lesion area in the aortic root significantly increased with a high-fat diet. Systemic cytokine balance shifted to a Th1-dominant state, and IL-12 mRNA in the arterial wall significantly increased with a high-fat diet; however, these findings were not observed with a normal diet. Conclusions: It was suggested that the proatherogenic effect of IL-18 is physiologically exerted exclusively with a high-fat diet through Th1 type immune responses, but not with a normal diet.