Human apolipoprotein A-IV reduces secretion of proinflammatory cytokines and atherosclerotic effects of a chronic infection mimicked by lipopolysaccharide.

OBJECTIVE Expression of human apolipoprotein (h-apo) A-IV in apoE-deficient (apoE(0)) mice (h-apoA-IV/E(0)) reduces susceptibility to atherosclerosis. Chronic infection mimicked by exposure to lipopolysaccharide (LPS) increases the size of atherosclerosis lesions in apoE(0) mice. Thus, we used h-apoA-IV/E(0) mice to determine whether h-apoA-IV plays a protective role after LPS administration. METHODS AND RESULTS We injected apoE(0), h-apoA-IV/E(0), and C57Bl/6 (wild-type) mice intraperitoneally with either LPS or phosphate-buffered saline (PBS) every week for 10 weeks. Atherosclerotic lesions were significantly smaller in h-apoA-IV/E(0) mice treated with LPS than in their apoE(0) counterparts. The titers of IgG2a and IgG2b autoantibodies to oxidized low-density lipoprotein (LDL) were higher in the LPS-group of h-apoA-IV/E(0) mice than in apoE(0) mice, suggesting that the Th1 response is stronger in the presence of h-apoA-IV. Lymphocytes from the blood, liver, spleen, and thymus of h-apoA-IV/E(0) mice treated with LPS produced less IL-4, INF-gamma, and TNF-alpha proinflammatory cytokines than their apoE(0) counterparts. Furthermore, we demonstrated that recombinant h-apoA-IV blocks the LPS-induced stimulation of monocytes. CONCLUSIONS The expression of h-apoA-IV in apoE(0) mice reduces the susceptibility to atherogenesis and decreases the secretion of proinflammatory cytokines after LPS administration.