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

Current research from both clinical and basic science perspectives indicate s that cytokines play an important role in the genesis of cardiovascular pa thology. Specifically, levels of cytokines such as interleukin-1 (IL-1), tu mor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) have been f ound to be elevated in both acute myocardial injury as well as situations o f 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. lir e recently reported that IL-1 beta induces a hypertrophic slate in cultured neonatal rat cardiac myocytes that differs from other well described hyper trophic phenotypes in terms of myocardial gene expression (such as skeletal alpha-actin, sACT), an effect that appeared to co-localize with that of th e 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. The se investigations indicate that sequences in and around the third upstream serum response element (SRE3) bind YY1 and are required for IL-1 beta media ted 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 tha t results in an increase in DNA-binding activity, (32)beta-labeling experim ents reveal an increase in phosphorylated YY1 in IL-1 beta treated cells an d phosphatase-treated myocyte nuclear proteins lose their ability to bind t o the YY1 site. In summary these results provide evidence that sequences wi thin the SRE3 of the skeletal actin promoter represent an IL-1 beta respons e clement and suggest that IL-1 beta activates the negative transcription f actor YY1 by both transcriptional and post-transcriptional mechanisms. (C) 2000 Academic Press.