Differential regulation of cardiac expression of IL-6 and TNF-alpha by A(2)- and A(3)-adenosine receptors

The proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interle ukin (IL)-6 have been implicated in the development of congestive heart fai lure. Adenosine inhibits the expression of TNF-alpha and IL-6 in macrophage s. We determined the effect of adenosine on cytokine expression in rat card iomyocytes and trabecular muscles obtained from patients with cardiomyopath y. In myocytes, adenosine suppressed TNF-alpha mRNA by 40% (P < 0.05) and i nduced a 4.7-fold increase in IL-6 mRNA(P < 0.05) with a twofold increase i n IL-6 protein release (P < 0.001). The effect on TNF-alpha could be replic ated by A(3) agonist. The effect on IL-6 could be replicated by A(3) agonis t, but not by A(1) and A(2) agonists, and was completely suppressed by A(3) antagonist. In human trabecular muscles, Aa agonist suppressed TNF-or mRNA by 60% (P < 0.05), but adenosine had no effect on IL-6 In the failing hear t, IL-6 was immunolocalized to inflammatory cells. Thus A(2) and A(3) recep tors differentially regulate cardiac expression of TNF-alpha and IL-6. Rat cardiomyocytes and the failing human heart respond differently to adenosine .