Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma.
We have previously shown that interferon-gamma (IFN-gamma) is a potent enhancer of atherogenesis. Interleukin-18 (IL-18) promotes inflammatory responses through release of IFN-gamma, 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-gamma 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 microm(2) P=0.004; saline versus IL-18 groups, respectively) and the aortic arch (3.1 +/- 0.3% versus 6.2 +/- 0.9% area, P=0.006). Exogenous IL-18 promoted a 4-fold increase in the number of lesion-associated T lymphocytes (11 +/- 3 versus 50 +/- 5 cells; P<0.0001) and cells expressing major histocompatability complex class II (9 +/- 3 versus 40 +/- 6 cells; P=0.0002). To determine the role of IFN-gamma production in this response, exogenous IL-18 was administered to apoE(-/-) mice that were IFN-gamma deficient. These studies demonstrated that lack of endogenous IFN-gamma ablated the effects of IL-18 on atherosclerosis. Therefore, these data strongly implicates IL-18 in the atherogenic process and suggests that IL-18 increases lesion development through enhancement of an inflammatory response involving an IFN-gamma-dependent mechanism. The full text of this article is available at http://www.circresaha.org.
Whitman
Stewart C
SC
Gill Heart Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY 40536-0230, USA.
Ravisankar
Punnaivanam
P
Daugherty
Alan
A
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002452:Cell Count; D002784:Cholesterol / Q000097:blood; D018450:Disease Progression; D004334:Drug Administration Schedule; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000172:deficiency; D020382:Interleukin-18 / Q000008:administration & dosage / Q000633:toxicity*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D013601:T-Lymphocytes / Q000473:pathology
D001057:Apolipoproteins E; D000949:Histocompatibility Antigens Class II; D020382:Interleukin-18; D008074:Lipoproteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; D002784:Cholesterol