Faculty Bibliography

Atherosclerosis is considered to be a chronic inflammatory disease of the arterial wall. Atherogenesis is accompanied by local production and release of inflammatory mediators, for which the macrophage is a major source. The proinflammatory cytokine, interferon (IFN)-gamma derived from T cells, is expressed at high levels in atherosclerotic lesions. IFN-gamma is the classic macrophage-activating factor, vital for both innate and adaptive immunity. It primes macrophages to produce chemokines and cytotoxic molecules and induces expression of genes that regulate lipid uptake. IFN-gamma is a key trigger for the formation and release of reactive oxygen species. IFN-gamma has important effects on endothelial cells, promoting expression of adhesion molecules. Atherogenic effects of IFN-gamma have been shown in murine models where exogenous administration enhances atherosclerotic lesion formation while knockout of IFN-gamma or its receptor reduces lesion size. IFN-gamma signaling is largely mediated by a Janus kinase (JAK) to signal transduction and activator of transcription (STAT)1 cytosolic factor pathway. A clear understanding of IFN-gamma effects on atherogenesis should enable development of novel targeted interventions for clinical use in the prevention and treatment of atherosclerosis. This review will discuss the actions of the cytokine IFN-gamma and its complex effects on cells involved in atherosclerosis.

Tumor necrosis factor- (TNF-) alpha is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-alpha monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-alpha and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) alpha, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-alpha alone or TNF-alpha with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-alpha significantly reduced both ABCA1 and LXR-alpha mRNA (to 68.5 +/- 1.59%, P < 0.05, and 41.2 +/- 0.25%, P < 0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-alpha effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-alpha. TNF-alpha treatment significantly reduces ABCA1 and LXR-alpha expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes.