INTERLEUKIN-1-BETA MODULATES THE GROWTH AND PHENOTYPE OF NEONATAL RATCARDIAC MYOCYTES

Mononuclear cell infiltration and local cytokine elaboration are hallm arks of inflammatory and immunologic heart diseases. To test the hypot hesis that cytokines can modulate cardiac myocyte growth and phenotype , myocytes cultured from neonatal rat hearts were exposed to IL-1 beta , an inflammatory cytokine prevalent in myocardial inflammation. IL-1 beta (2 ng/ml, 24 h) increased [H-3]leucine incorporation by 30 +/- 4% (P < 0.001, n = 29) and net cellular protein content by 20 +/- 4% (P < 0.001, n = 27), but had no effect on DNA synthesis. Northern hybridi zation showed that IL-1 beta increased prepro-atrial natriuretic facto r (ANF) mRNA (5.8 +/- 1.5-fold, P < 0.01, n = 13) and beta-myosin heav y chain (beta-MHC) mRNA (> 10-fold, n = 4), and decreased mRNA levels for sarcoplasmic reticulum Ca2+-ATPase (SERCA2) (-46 +/- 7%; P < 0.001 ; n = 11), calcium release channel(CRC) (-65 +/- 11%,P < 0.001, n = 8) and voltage-dependent calcium channel (VDCC) (-53 +/- 7%, P < 0.001, n = 8). N-G-monomethyl-L-arginine (1 mM), an inhibitor of nitric oxide (NO) synthesis, did not inhibit the IL-1 beta-induced protein synthes is or changes in mRNA levels. In ventricular myocardium obtained from adult rats treated with lipopolysaccharide (4 mg/kg intraperitoneally 18 h) to stimulate systemic cytokine production, there were changes in the mRNA levels for beta-MHC (6 +/- 1-fold, P < 0.01, n = 4), SERCA2 (-65 +/- 4%, P < 0.0001, n = 4), CRC (-67 +/- 5%, P < 0.001, n = 4), a nd VDCC ( -58 +/- 5%, P < 0.001; n = 4) that were qualitatively simila r to those observed in cultured myocytes. Thus,IL-1 beta, acting via a n NO-independent mechanism, caused myocyte hypertrophy associated with induction of fetal genes (ANF and P-MHC) and downregulation of three important calcium regulatory genes (SERCA2, CRC, and VDCC). IL-1 beta may contribute to the abnormal structural and functional alterations o f cardiac myocytes in conditions marked by mononuclear cell infiltrati on.