Interferon-gamma and lipopolysaccharide potentiate monocyte tissue factor induction by C-reactive protein - Relationship with age, sex, and hormone replacement treatment

Background-Elevated plasma levels of C-reactive protein (CRP) in population studies and in patients with unstable coronary syndromes are predictive of future adverse events, including cardiac death and myocardial infarction, implicating inflammation in pathogenesis. Although CRP is considered a mark er of inflammation, it induces monocyte tissue factor (TF) and may play a p rothrombotic role in atherosclerosis and its complications. Methods and Results-Peripheral blood mononuclear cells (PBMCs) from 79 heal thy men and women aged 26 to 83 years and 21 healthy postmenopausal women t aking hormone replacement therapy (HRT) were stimulated with CRP, lipopolys accharide (LPS), interferon-gamma (IFN), or their combination. Levels of CR P in the normal range (1 to 5 mu g/mL) increased basal monocyte TF 4- to 6- fold and 40-fold at higher concentrations (25 mu g/mL). Coincubation of LPS with CRP produced a greater-than-additive response. IFN did not induce TF but synergized with CRP to approximately double activity. There was a strik ing positive correlation between age and monocyte TF induction, with a dram atic rise on monocytes from postmenopausal women that was not apparent on c ells from women taking HRT. Conclusions-Synergy between CRP and inflammatory mediators may play a direc t prothrombotic role in the pathogenesis of coronary atherosclerosis and it s acute complications by increasing monocyte/macrophage TF. This may contri bute to age and sex differences in coronary events and to the protective ef fects of HRT.