IL-18 – a destabilizer of atherosclerotic disease

Abstract

Globally, mortality from atherosclerotic disease (AD) (i.e. stroke, myocardial infarction and unstable angina) is on the increase. AD is characterized by an initial deposition of modified lipids, in the form of fatty-streak lesions, in the subendothelial space of large arteries, followed by an accumulation of macrophage foam cells and activated T cells in the lesions. Sustained, elevated serum levels of cholesterol cause this microenvironment to become atherogenic; smooth-muscle cells immigrate, proliferate and produce numerous extracellular matrix proteins that form fibrous plaques. As these plaques evolve, the vessel reaches a state of instability, poised to rupture, leading ultimately to acute episodes of life-threatening ischemia. The development of cholesterol-lowering drugs, particularly the statins, has provided significant therapeutic benefits. However, this targeted approach remains insufficient to abrogate the progression of AD completely.Two landmark studies conducted in the laboratories of Tedgui and Chvatchko have opened a new chapter of novel therapeutic approaches for AD, centering on interleukin-18 (IL-18) [1xExpression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Mallat, Z. et al. Circulation. 2001; 104: 1598–1603Crossref | PubMedSee all References, 2xInterleukin-18/interleukin-18BP signaling modulates atherosclerotic-lesion development and stability. Mallat, Z. et al. Circ. Res. 2001; 89: e41–e45Crossref | PubMedSee all References]. This cytokine synergizes with IL-12 to promote the production of interferon γ and also, acts directly to influence the activities of proinflammatory cytokines, adhesion molecules and caspases, and the interaction between Fas and Fas ligand. The investigators observed that IL-18 is expressed highly in human carotid atherosclerotic plaques, particularly by the resident macrophages [1xExpression of interleukin-18 in human atherosclerotic plaques and relation to plaque instability. Mallat, Z. et al. Circulation. 2001; 104: 1598–1603Crossref | PubMedSee all References][1]. In addition, the IL-18 receptor is expressed by these macrophages and the adjacent endothelial cells. The most stunning result was the association of a significantly higher level of IL-18 with the samples from patients presenting with unstable plaque histology compared with those with a stable phenotype, clearly linking IL-18 to the advanced stage of AD. But, is IL-18 a pro- or anti-atherogenic mediator?Genetically targeted apoE−/− mice have contributed significantly to our understanding of AD pathogenesis. These mice have elevated plasma cholesterol levels, which, by 14 weeks of age, have resulted in atherogenesis within the aortic sinus, whereas the thoracic aorta remains lesion-free. These characteristics allow the evaluation of disease progression in established and de novo plaques when treatments are begun at this time point. Using 14-week old apoE−/− mice, the investigators delivered exogenous IL-18-binding protein (IL-18BP), a naturally occurring molecule that neutralizes IL-18, for nine weeks by intramuscular electrotransfer technology [2xInterleukin-18/interleukin-18BP signaling modulates atherosclerotic-lesion development and stability. Mallat, Z. et al. Circ. Res. 2001; 89: e41–e45Crossref | PubMedSee all References][2]. At 23 weeks of age, the arteries of mice receiving IL-18BP had a profound reduction in the formation of new lesions, as well as signs of recovery in the established lesions, including minimal leukocyte infiltration and apoptosis, with a concomitant increase in collagen content, compared with control mice. As such, this study provides evidence of the pathogenic link between IL-18 and AD. Despite the caveats associated with studies performed in animals, combining the results of these two studies implicates IL-18 as being clearly deleterious for AD and supports impressively a role in the clinic for IL-18 inhibitors.