Elsevier

Atherosclerosis

Volume 148, Issue 2, 1 February 2000, Pages 209-214
Atherosclerosis

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

https://doi.org/10.1016/S0021-9150(99)00463-3Get rights and content

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-α (TNF-α), 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.

Section snippets

Inflammation, infection and coronary heart disease

Inflammation leads to the localised recruitment of neutrophils and monocytes, and the presence of activated macrophages in the cap of the atherosclerotic plaque [1] has led to suggestions that they contribute to plaque rupture through effects on matrix metalloproteinases [2]. Pathological and intervention studies have implicated organisms like Chlamydia in initiating or maintaining such inflammation [3], [4], but there is also evidence that elevated concentrations of the acute phase reactant,

How could IL-6 increase atherothrombotic risk?

IL-6 might play a key role in the development of coronary disease through a number of different mechanisms; metabolic, endothelial and coagulant. IL-6 increases basal glucose uptake, alters insulin sensitivity, increases the release of adhesion molecules by the endothelium and increases the hepatic release of fibrinogen, as well as having procoagulant effects on platelets. There is a close relationship between circulating concentrations of CRP, IL-6 and TNF-α, with the components of the insulin

Obesity, adipose tissue and IL-6

Recent observations from our laboratory have suggested a previously unsuspected source for this cytokine. Using the method of arteriovenous difference measures across a subcutaneous adipose tissue bed and radio-xenon estimates of adipose tissue blood flow, net IL-6 production by human subcutaneous adipose tissue has been demonstrated in vivo [32]. In healthy men and women the production of IL-6, as well as systemic concentrations, increase with adiposity and we have estimated that as much as a

Testing the IL-6 hypothesis

The paradigm shown in Fig. 1 suggests a number of possible experiments to test specific parts of the overall scheme. However, because of the time scale of the evolution of atherothrombotic disease it is more problematic to test the role of IL-6 in CHD directly. Any test of the role of IL-6 will require other evidence, such as from animal models with overexpression or knockout of the IL-6 gene, or from the use of monoclonal antibodies or antagonists. Ultimately, prospective studies will be

Acknowledgements

The work outlined in this article has been supported by grants from the Medical Research Council, the British Heart Foundation (RG95007; SP/98003), the Wellcome Trust, the British Diabetic Association, the Sir Jules Thorn Charitable Trust (97/18A), the National Institute of Ageing, and Biomed 2.

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    On behalf of the University College London Interleukin-6 Group. Additional membership: Dr Simon Coppack, Professor Patrick Vallance, Professor John Martin, Professor Michael Marmot, Dr Eric Brunner and Louise Flower.

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