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.


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.
Recalde
Delia
D
Unité d'Expression des Gènes Eucaryotes, Institut Pasteur, Paris, France.
Ostos
Maria A
MA
Badell
Edgar
E
Garcia-Otin
Angel-Luis
AL
Pidoux
Josette
J
Castro
Graciela
G
Zakin
Mario M
MM
Scott-Algara
Daniel
D
D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000502:physiology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001773:Blood Cells / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007239:Infections; D008055:Lipids / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology / Q000633:toxicity; D008077:Lipoproteins, LDL / Q000276:immunology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D016131:Lymphocyte Subsets / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology
D001054:Apolipoproteins A; D001057:Apolipoproteins E; D001323:Autoantibodies; D016207:Cytokines; D008055:Lipids; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D011993:Recombinant Fusion Proteins; C022205:apolipoprotein A-IV; C099252:oxidized low density lipoprotein