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

Abstract

There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological 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 development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall 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 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose 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.

• Authors: J S Yudkin, M Kumari, S E Humphries, V Mohamed-Ali
• Journal: Atherosclerosis (Atherosclerosis) Vol. 148 Issue 2 Pg. 209-14 (Feb 2000) ISSN: 0021-9150 [Print] Ireland
• PMID: 10657556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Interleukin-6

Topics

• Animals
• Arteriosclerosis (etiology)
• Coronary Disease (etiology)
• Humans
• Interleukin-6 (physiology)
• Obesity (complications)
• Risk Factors
• Stress, Physiological (complications)
• Thrombosis (etiology)
• Vasculitis (complications)