The Journal of Experimental Medicine
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Published 22 January 2002. doi:10.1084/jem.20011022
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© Rockefeller University Press, 0022-1007/2002/1/245/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 2, January 21, 2002 245-257

Original Article

 Expression of Interleukin (IL)-18 and Functional IL-18 Receptor on Human Vascular Endothelial Cells, Smooth Muscle Cells, and Macrophages : Implications for Atherogenesis



Norbert Gerdes, Galina K. Sukhova, Peter Libby, Rebecca S. Reynolds, James L. Young and Uwe Schönbeck

Leducq Center for Cardiovascular Research, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Address correspondence to Uwe Schönbeck, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., LMRC 307, Boston, MA 02115. Phone: 617-278-0455; Fax: 617-732-6961; E-mail: uschoenbeck{at}rics.bwh.harvard.edu

Although considerable evidence implicates the cytokine interferon (IFN)-{gamma} in atherogenesis, the proximal inducers and the range of sources of its expression remain unknown. This study tested the hypothesis that interleukin (IL)-18 regulates IFN-{gamma} expression during atherogenesis. Indeed, human atheroma in situ expressed IL-18 and elevated levels of its receptor subunits, IL-18R{alpha}/ß, compared with nondiseased arterial tissue. IL-18 occurred predominantly as the mature, 18-kD form and colocalized with mononuclear phagocytes (MØ), while endothelial cells (ECs), smooth muscle cells (SMCs), and MØ all expressed IL-18R{alpha}/ß. Correspondingly in vitro, only MØ expressed IL-18, while all three cell types displayed the IL-18R{alpha}/ß complex constitutively, exhibiting enhanced expression upon stimulation with LPS, IL-1ß, or tumor necrosis factor (TNF)-{alpha}. IL-18 signaling evoked effectors involved in atherogenesis, e.g., cytokines (IL-6), chemokines (IL-8), intracellular adhesion molecules (ICAM)-1, and matrix metalloproteinases (MMP-1/-9/-13), demonstrating functionality of the receptor on ECs, SMCs, and MØ. Finally, IL-18, particularly in combination with IL-12, induced the expression of IFN-{gamma} in cultured MØ and, surprisingly, in SMCs (but not in ECs). The expression of functional IL-18 and IL-18 receptor on human atheroma-associated ECs, SMCs, and MØ, and its unexpected ability to induce IFN-{gamma} expression in SMCs, suggests a novel paracrine proinflammatory pathway operating during atherogenesis.

Key Words: atherosclerosis • inflammation • IL-18/IL-18R • interferon-{gamma} • cytokines


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