Published online before print January 17, 2002, doi: 10.1161/hh0202.105292
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© 2002 American Heart Association, Inc.
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Interleukin-18 Enhances Atherosclerosis in Apolipoprotein E-/- Mice Through Release of Interferon-
From the Gill Heart Institute, Division of Cardiovascular Medicine, University of Kentucky, Lexington, Ky. Present address for S.C.W. is University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Correspondence to Alan Daugherty, PhD, Division of Cardiovascular Medicine, Gill Heart Institute, Sanders Brown, Rm 424, University of Kentucky, Lexington, KY 40536-0230. E-mail adaugh{at}uky.edu
Abstract
We have previously shown that interferon-
(IFN-) is a potent enhancer of atherogenesis. Interleukin-18 (IL-18) promotes inflammatory responses through release of IFN-, 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- 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 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- production in this response, exogenous IL-18 was administered to apoe-/- mice that were IFN- deficient. These studies demonstrated that lack of endogenous IFN- 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-–dependent mechanism. The full text of this article is available at http://www.circresaha.org.
Key Words: immunology • inflammation • cholesterol • atherosclerosis • apolipoprotein E
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