Inflammation, obesity, stress and coronary heart disease: is interleukin-6the link?

There is mounting evidence that inflammation plays a role in the developmen t of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemi ological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the developm ent of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive prote in (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is ass ociated with elevated levels of fibrinogen, a strong risk factor for CHD, w ith autocrine and paracrine activation of monocytes by IL-6 in the vessel w all contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 de creases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasm a, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smoot h muscle cells (SMC) express IL-6, suggesting a role for this cytokine alon g with interleukin-l (IL-1) and tumour necrosis factor-a (TNF-a), in the pr ogression of atherosclerosis. Both these cytokines induce the release of IL -6 from several cell types, including SMC, During vascular injury SMC are e xposed to platelets or their products, and cytokine production by SMC furth er contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is asso ciated with central obesity, hypertension and insulin resistance. Thus we p ropose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions. (C ) 2000 Elsevier Science Ireland Ltd. All rights reserved.