IL-1β increases abundance and activity of the negative transcriptional regulator yin yang-1 (YY1) in neonatal rat cardiac myocytes

Current research from both clinical and basic science perspectives indicates that cytokines play an important role in the genesis of cardiovascular pathology. Specifically, levels of cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) have been found to be elevated in both acute myocardial injury as well as situations of chronic dysfunction. Further, therapies directed primarily at interfering with cytokine action have suggested that such an immunomodulatory approach may be beneficial in some of these circumstances of myocardial injury. lire recently reported that IL-1 beta induces a hypertrophic slate in cultured neonatal rat cardiac myocytes that differs from other well described hypertrophic phenotypes in terms of myocardial gene expression (such as skeletal alpha-actin, sACT), an effect that appeared to co-localize with that of the negative regulator yin yang-1 (YY1),(1) In the present study, we further localize the area in the sACT promoter responsible for the IL-1 effect. These investigations indicate that sequences in and around the third upstream serum response element (SRE3) bind YY1 and are required for IL-1 beta mediated repression. This element is also capable of transferring both IL-1 beta and YY1-mediated transcriptional repression to a heterologous promoter, In support of an IL-1 beta induced post-translational modification of YY1 that results in an increase in DNA-binding activity, (32)beta-labeling experiments reveal an increase in phosphorylated YY1 in IL-1 beta treated cells and phosphatase-treated myocyte nuclear proteins lose their ability to bind to the YY1 site. In summary these results provide evidence that sequences within the SRE3 of the skeletal actin promoter represent an IL-1 beta response clement and suggest that IL-1 beta activates the negative transcription factor YY1 by both transcriptional and post-transcriptional mechanisms. (C) 2000 Academic Press.