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-κB has long been known to play pivotal roles in immune and inflammatory responses, and furthermore NF-κB has been implicated in the regulation of epidermal homeostasis. Recent studies have established that p65/RelA is a potent repressor of PPARδ-mediated transactivation in human keratinocytes. In this article we further investigate the molecular mechanisms dictating the NF-κB-dependent repression of PPARδ in human keratinocytes. We demonstrate that repression is unique to p65/RelA, as no other member of the NF-κB family had an impact on PPARδ-mediated transactivation. Interestingly, our results show that p65/RelA only represses PPARδ-dependent transactivation when PPARδ 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 PPARδ, p65/RelA, and HDAC1 is formed in vivo. Finally, we demonstrate that TSA relieves tumor necrosis factor-α (TNFα)-induced repression of PPARδ-mediated transactivation of the PPARδ target gene adipose differentiation-related protein (ADRP) indicating that cross-talk between PPARδ and NF-κB is of biological significance in human keratinocytes