INTERLEUKIN-1-BETA IS A NEGATIVE TRANSCRIPTIONAL REGULATOR OF ALPHA(1)-ADRENERGIC INDUCED GENE-EXPRESSION IN CULTURED CARDIAC MYOCYTES

We recently reported that interleukin-1 beta (IL-1 beta) induces a nov el form of cardiac myocyte hypertrophy characterized by an increase in protein content but an absence of the fetal program of skeletal alpha -actin or beta-myosin heavy chain (beta-MHC) gene expression (Palmer, J. N., Hartogensis, W. E., Fatten, M., Fortuin, F. D., and Long, C. S. (1995) J. Clin. Invest. 95, 2555-2564). Because of the apparent dispa rity between this myocardial phenotype and that seen with other hypert rophic agents in culture, such as catecholamines, we investigated the effect of IL-1 beta on alpha(1)-induced cardiomyocyte hypertrophy. Alt hough there was no augmentation in total protein when IL-1 beta and ph enylephrine were given simultaneously, IL-1 beta attenuated the increa se in contractile protein mRNAs (skeletal alpha-actin and beta-MHC) in response to phenylephrine. Transient transfection studies with skelet al alpha-actin and beta-MHC promoter constructs linked to the chloramp henicol acetyltransferase (CAT)-reporter gene indicate that repression occurred at the level of gene transcription. In view of the previousl y reported activity of the zinc finger protein YY1 in the negative reg ulation of the skeletal alpha-actin promoter in cardiomyocytes (MacLel lan, W. R., Lee, T. C., Schwartz, R. J., and Schneider, M. D. (1994) J . Biol. Chem. 269, 16754-16760), we investigated the potential role of this factor in the IL-1 beta-mediated effects. Using transient transf ection, we found that a mutation in the YY1 binding site of the skelet al alpha-actin promoter abolished the inhibitory effect of IL-1 beta. We further found that the 127-base pair fragment of the skeletal alpha -actin promoter required for the IL-1 beta effect is also required for inhibition by the overexpression of YY1 in the myocytes. Furthermore, increased levels of YY1 protein are found in IL-1 beta treated myocyt es. Taken together these results suggest that the repression of contra ctile protein gene transcription by IL-1 beta may be due, at least in part, to activation of the negative transcription factor YY1.