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.