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(Circulation Research. 2001;89:e41.)
© 2001 American Heart Association, Inc.

UltraRapid Communication

Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Atherosclerotic Lesion Development and Stability

Ziad Mallat^*, Anne Corbaz^*, Alexandra Scoazec, Pierre Graber, Sami Alouani, Bruno Esposito, Yves Humbert, Yolande Chvatchko, Alain Tedgui

From Institut National de la Santé et de la Recherche Médicale, Unité 541 (Z.M., A.S., B.E., A.T.), et Institut Fédératif de Recherche Paris VII, Hôpital Lariboisière, France; and Serono Pharmaceutical Research Institute (A.C., P.G., S.A., Y.H., Y.C.), Geneva, Switzerland.

Correspondence to Ziad Mallat, MD, PhD, INSERM U541, 41, Bd de la Chapelle, 75475 Paris cedex 10. E-mail ziad.mallat{at}inserm.lrb.ap-hop-paris.fr; or to Yolande Chvatchko, PhD, Serono Pharmaceutical Research Institute, 1228 Plan-Les-Ouates, Geneva, Switzerland. E-mail yolande.chvatchko@serono.com

Abstract — Interleukin (IL)-18 is the interferon-–inducing factor and has other proinflammatory properties. The precise role of IL-18 in immunoinflammatory diseases remains poorly understood. In this study, we show that in vivo electrotransfer of an expression-plasmid DNA encoding for murine IL-18 binding protein (BP) (the endogenous inhibitor of IL-18) prevents fatty streak development in the thoracic aorta of apoE knockout mice and slows progression of advanced atherosclerotic plaques in the aortic sinus. More importantly, transfection with the IL-18BP plasmid induces profound changes in plaque composition (decrease in macrophage, T cell, cell death, and lipid content and increase in smooth muscle cell and collagen content) leading to a stable plaque phenotype. These results identify for the first time a critical role for IL-18/IL-18BP regulation in atherosclerosis and suggest a potential role for IL-18 inhibitors in reduction of plaque development/progression and promotion of plaque stability. The full text of this article is available at http://www.circresaha.org.

Key Words: atherosclerosis • inflammation • interleukin • cytokines

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