Low Level Tumor Necrosis Factor-Alpha Protects Cardiomyocytes Against High Level Tumor Necrosis Factor-Alpha: Brief Insight into a Beneficial Paradox

摘要

Whether tumor necrosis factor-alpha (TNF alpha) caused beneficial or detrimental cardiovascular effects remains poorly defined. Anti-TNF alpha agents improved cardiac end points in chronic rheumatic diseases characterized by progressive deterioration of cardiac function. In contrast, anti-TNF alpha agents did not always improve but actually worsened cardiac function in non-rheumatic patients with heart failure (HF), in spite of that HF usually accompanies with high circulating levels of TNF alpha. To shed light on these mixed findings, we characterized the effects of TNF alpha in H9c2 cardiomyocytes. Cells were incubated for 24 h with increasing concentrations of TNF alpha, hydrogen peroxide, aminotriazole, or etoposide. Posttreatment cell viability was assessed by antimycin A-inhibitable reduction of 3-(4,dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, and the IC50 value of each test compound was defined. H9c2 cells were also preconditioned with a low non-toxic concentration of TNF alpha and then re-challenged with increasing concentrations of TNF alpha and other stressor agents. In re-challenge experiments, all of the IC50 values increased significantly, with the IC50 value of TNF alpha increasing approximately 16-fold. TNF alpha preconditioning increased cardiomyocytes shedding of the external portion of transmembrane type 1 and type 2 TNF alpha receptors [(soluble TNF alpha receptors (sTNFR)]. Levels of survival-oriented soluble TNFR2 (sTNFR2) always exceeded those of death-oriented sTNFR1. When exposed to TNF alpha at its IC50 value, preconditioned cardiomyocytes showed an increased release of sTNFR2 but not sTNFR1. These results denoted that preconditioning by "low TNF alpha" helped cardiomyocyte to withstand toxicity from "high TNF alpha" or other agents. These results also suggested that beneficial or detrimental effects of anti-TNF alpha agents might well depend on whether these agents spared or intercepted discrete amounts of TNF alpha that preconditioned cardiomyocytes and made them more resistant to high concentrations of TNF alpha.