CYTOKINES REGULATE VASCULAR FUNCTIONS RELATED TO STABILITY OF THE ATHEROSCLEROTIC PLAQUE

The cytokines are multipotent mediators of inflammation and immunity t hat can affect key functions of vascular wall cells. Growing evidence suggests that cytokines participate as autocrine or paracrine mediator s in atherogenesis, as cells in lesions can both produce and respond t o these mediators. The functions of vascular wall cells regulated by c ytokines may influence lesion initiation, progression, or complication . For example, cytokines can regulate the expression of adhesion molec ules crucial to the recruitment of leukocytes to lesions, including va scular cell adhesion molecule-1 (VCAM-1). Cytokines such as interleuki n-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can regulate th e production of monocyte chemoattractant protein-1 (MCP-1), a potentia l signal for directed migration of monocytes into the intima. Cytokine s can also regulate genes that encode other growth factors and cytokin es themselves. TNF-alpha can induce IL-1 mRNA in human endothelial (EC ) and smooth-muscle cells (SMC). IL-1 and TNF-alpha can augment the pr oduction by vascular cells of macrophage-colony stimulating factor (M- CSF), which may promote growth and activation of mononuclear phagocyte s. Cytokines can exert both pro- and antiatherogenic actions. Activate d T cells in human atheroma may secrete the lymphokine IFN-gamma, an i nhibitor of SMC proliferation. Cytokines influence vasomotor tone in a rteries, e.g., by inducing a form of nitric oxide synthase, the enzyme that synthesizes the vasodilatory nitric oxide radical. The cytokines also modulate endothelial functions that govern the formation and sta bility of blood thrombi. Finally, in the late stages of the disease, m atrix metalloproteinases derived from macrophages or smooth-muscle cel ls themselves may contribute to weakening of the fibrous cap in the vu lnerable shoulder area, promoting plaque rupture and occlusive thrombo sis, culminating in the dramatic clinical manifestations of atheroscle rosis, including myocardial infarction and stroke. Thus, cytokines can influence multiple aspects of atherogenesis and provide new and inter esting targets for therapeutic intervention.