INCREASED SECRETION OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA BY MONONUCLEAR LEUKOCYTES IN PATIENTS WITH ISCHEMIC-HEART-DISEASE -RELEVANCE IN SUPEROXIDE ANION GENERATION

Background There is growing evidence for a pathogenic role for cytokin es in atherogenesis. The presence of certain cytokines has been docume nted in human atherosclerotic vessels. This study was designed to inve stigate cytokine production by mononuclear leukocytes from patients wi th ischemic heart disease. Methods and Results We measured kinetics of secretion of tumor necrosis factor-alpha (TNF-alpha) and interferon-g amma (IFN-gamma) by mononuclear leukocytes from 8 control subjects, 10 patients with stable angina pectoris, and 10 patients with unstable a ngina pectoris. Mononuclear leukocytes were isolated and incubated wit h or without the plant lectin mitogen concanavalin A for 48 hours. TNF -alpha and IFN-gamma secretion were measured by ELISA. The effect of T NF-alpha and IFN-gamma on superoxide radical generation by neutrophils was also examined. Secretion of both TNF-alpha and IFN-gamma by monon uclear leukocytes increased progressively over 48 hours, and it was co nsistently higher (P<.02) in patients compared with control subjects. A similar increase in cytokine secretion was observed in patients with stable or unstable angina pectoris. In addition, there was no relatio n between the severity of coronary artery disease by angiography and c ytokine secretion. Basal neutrophil superoxide radical generation was increased in patients with ischemic heart disease, and incubation with cytokines failed to further stimulate superoxide generation in these patients. Conclusions Similar increases in cytokine secretion by monon uclear leukocytes in stable or unstable angina pectoris indicate that the increased cytokine release is not a nonspecific inflammatory respo nse in acute myocardial ischemia. Increased cytokine secretion in isch emic heart disease may play a role in superoxide radical generation, e ndothelial injury, deposition and activation of cellular elements on t he vessel wall, and possibly in the progression of atherosclerosis.