HDAC activity is required for p65/RelA-dependent repression of PPARδ-mediated transactivation in human keratinocytes

Peroxisome proliferator-activated receptors (PPARs) play a key role in differentiation, inflammation, migration, and survival of epidermal keratinocytes. The NF-kappa B has long been known to play pivotal roles in immune and inflammatory responses, and furthermore NF-kappa B has been implicated in the regulation of epidermal homeostasis. Recent studies have established that p65/RelA is a potent repressor of PPAR delta-mediated transactivation in human keratinocytes. In this article we further investigate the molecular mechanisms dictating the NF-kappa B-dependent repression of PPAR delta in human keratinocytes. We demonstrate that repression is unique to p65/RelA, as no other member of the NF-kappa B family had an impact on PPAR delta-mediated transactivation. Interestingly, our results show that p65/RelA only represses PPAR delta-dependent transactivation when PPAR delta is bound to DNA via its DNA-binding domain. We show that repression is sensitive to inhibition of histone deacetylases (HDACs) by tricostatin A (TSA), suggesting that HDAC activity is indispensable for p65/RelA-mediated repression. Accordingly, we demonstrate that a ternary complex consisting of PPAR delta, p65/RelA, and HDAC1 is formed in vivo. Finally, we demonstrate that TSA relieves tumor necrosis factor-alpha (TNF alpha)-induced repression of PPAR delta-mediated transactivation of the PPAR delta target gene adipose differentiation-related protein (ADRP) indicating that cross-talk between PPAR delta and NF-kappa B is of biological significance in human keratinocytes.