Increased secretion of tumor necrosis factor-alpha and interferon-gamma by mononuclear leukocytes in patients with ischemic heart disease. Relevance in superoxide anion generation.

Abstract

BACKGROUND There is growing evidence for a pathogenic role for cytokines in atherogenesis. The presence of certain cytokines has been documented in human atherosclerotic vessels. This study was designed to investigate cytokine production by mononuclear leukocytes from patients with ischemic heart disease. METHODS AND RESULTS We measured kinetics of secretion of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) by mononuclear leukocytes from 8 control subjects, 10 patients with stable angina pectoris, and 10 patients with unstable angina pectoris. Mononuclear leukocytes were isolated and incubated with or without the plant lectin mitogen concanavalin A for 48 hours. TNF-alpha and IFN-gamma secretion were measured by ELISA. The effect of TNF-alpha and IFN-gamma on superoxide radical generation by neutrophils was also examined. Secretion of both TNF-alpha and IFN-gamma by mononuclear leukocytes increased progressively over 48 hours, and it was consistently 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 relation between the severity of coronary artery disease by angiography and cytokine 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 mononuclear leukocytes in stable or unstable angina pectoris indicate that the increased cytokine release is not a nonspecific inflammatory response in acute myocardial ischemia. Increased cytokine secretion in ischemic heart disease may play a role in superoxide radical generation, endothelial injury, deposition and activation of cellular elements on the vessel wall, and possibly in the progression of atherosclerosis.