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Biotech / Medical : Regeneron Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (649)	4/30/2002 8:13:26 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 3561

Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 9, 6280-6285, April 30, 2002 Medical Sciences Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size Cecilia M. Devlin, George Kuriakose, Emmet Hirsch, and Ira Tabas, Departments of Medicine and Anatomy & Cell Biology, Columbia University, 630 West 168th Street, New York, NY 10032; and Department of Obstetrics and Gynecology, Northwestern University, Evanston, IL 60201 Edited by S. M. McCann, Pennington Biomedical Research Center, Baton Rouge, LA, and approved March 11, 2001 (received for review June 26, 2001) Inflammatory cytokines have been linked to atherosclerosis by using cell culture models and acute inflammation in animals. The goal of this study was to examine lipoprotein levels and early atherosclerosis in chronic animal models of altered IL-1 physiology by using mice with deficient or excess IL-1 receptor antagonist (IL-1ra). IL-1ra knockout C57BL/6J mice fed a cholesterol/cholate diet for 3 mo had a 3-fold decrease in non-high-density lipoprotein cholesterol and a trend toward increased foam-cell lesion area compared to wild-type littermate controls. IL-1ra transgenic/low-density lipoprotein receptor (LDLR) knockout mice fed a cholesterol-saturated fat diet for 10 wk showed a 40% increase in non-high-density lipoprotein cholesterol, consistent with the IL-1ra knockout data, although there was no change in lesion size. When these IL1-ra overexpressing transgenic mice on the LDLR knockout background were fed a high-cholesterol/high-fat diet containing cholate, however, a statistically significant 40% decrease in lesion area was observed compared to LDLR knockout mice lacking the transgene. By immunohistochemistry, IL-1ra was present in C57BL/6J and LDLR knockout aortae, absent in IL-1ra knockout aortae, and present at high levels in LDLR knockout/IL-1ra transgene aortae. In summary, IL-1ra tended to increase plasma lipoprotein levels and, when fed a cholate-containing diet, decrease foam-cell lesion size. These data demonstrate that in selected models of murine atherosclerosis, chronic IL-1ra depletion or overexpression has potentially important effects on lipoprotein metabolism and foam-cell lesion development.