Interleukins in atherosclerosis: molecular pathways and therapeutic potential.
Interleukins are considered to be key players in the chronic vascular inflammatory response that is typical of atherosclerosis. Thus, the expression of proinflammatory interleukins and their receptors has been demonstrated in atheromatous tissue, and the serum levels of several of these cytokines have been found to be positively correlated with (coronary) arterial disease and its sequelae. In vitro studies have confirmed the involvement of various interleukins in pro-atherogenic processes, such as the up-regulation of adhesion molecules on endothelial cells, the activation of macrophages, and smooth muscle cell proliferation. Furthermore, studies in mice deficient or transgenic for specific interleukins have demonstrated that, whereas some interleukins are indeed intrinsically pro-atherogenic, others may have anti-atherogenic qualities. As the roles of individual interleukins in atherosclerosis are being uncovered, novel anti-atherogenic therapies, aimed at the modulation of interleukin function, are being explored. Several approaches have produced promising results in this respect, including the transfer of anti-inflammatory interleukins and the administration of decoys and antibodies directed against proinflammatory interleukins. The chronic nature of the disease and the generally pleiotropic effects of interleukins, however, will demand high specificity of action and/or effective targeting to prevent the emergence of adverse side effects with such treatments. This may prove to be the real challenge for the development of interleukin-based anti-atherosclerotic therapies, once the mediators and their targets have been delineated.
von der Thüsen
Jan H
JH
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands. thuesen@lacdr.leidenuniv.nl
Kuiper
Johan
J
van Berkel
Theo J C
TJ
Biessen
Erik A L
EA
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000494:pharmacology*; D007378:Interleukins / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D018836:Inflammation Mediators; D007378:Interleukins