EXPRESSION AND FUNCTIONAL-SIGNIFICANCE OF TUMOR-NECROSIS-FACTOR RECEPTORS IN HUMAN MYOCARDIUM

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine wi th potent negative inotropic properties, is elaborated in septic shock , acute myocarditis, reperfusion injury, and congestive heart failure. TNF-alpha acts by binding to two specific receptors: TNFR1 and TNFR2. However, neither the presence nor the significance of TNF receptors h as been studied in the adult mammalian heart. Methods and Results In t he present study, we showed that the adult heart expresses mRNA and re ceptor proteins for TNFR1 and TNFR2. Moreover, immunohistochemical sta ining studies localized TNFR1 and TNFR2 to the cardiac myocyte, provid ing a potential signaling pathway for the deleterious effects of TNF-a lpha. The functional significance of the expression of TNFR1 and TNFR2 was explored with the use of a simple cell motion assay in which we a ssessed the effect(s) of TNF-alpha mutants known to bind selectively t o human TNFR1 and TNFR2. We showed that the negative inotropic effect of wild-type TNF-alpha in isolated feline cardiac myocytes was mimicke d by the TNF mutant that binds to TNFR1, whereas the TNF mutant that b inds to TNFR2 had no significant effect on cell motion. Conclusions Re sults of the present study show that the adult human heart expresses b oth mRNA and receptor proteins for TNFR1 and TNFR2; moreover, the nega tive inotropic effects of TNF-alpha in adult cardiac myocytes appear t o be initiated by activation of TNFR1.