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

Research output: Contribution to journalJournal articlepeer-review

  • Lene Aarenstrup
  • Esben Noerregaard Flindt
  • Kristian Otkjaer
  • Morten Kirkegaard
  • Jens Skorstensgaard Andersen
  • Kristiansen, Karsten
Peroxisome proliferator-activated receptors (PPARs) play a key role in differentiation, inflammation, migration, and survival of epidermal keratinocytes. The NF-kappaB has long been known to play pivotal roles in immune and inflammatory responses, and furthermore NF-kappaB has been implicated in the regulation of epidermal homeostasis. Recent studies have established that p65/RelA is a potent repressor of PPARdelta-mediated transactivation in human keratinocytes. In this article we further investigate the molecular mechanisms dictating the NF-kappaB-dependent repression of PPARdelta in human keratinocytes. We demonstrate that repression is unique to p65/RelA, as no other member of the NF-kappaB family had an impact on PPARdelta-mediated transactivation. Interestingly, our results show that p65/RelA only represses PPARdelta-dependent transactivation when PPARdelta 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 PPARdelta, p65/RelA, and HDAC1 is formed in vivo. Finally, we demonstrate that TSA relieves tumor necrosis factor-alpha (TNFalpha)-induced repression of PPARdelta-mediated transactivation of the PPARdelta target gene adipose differentiation-related protein (ADRP) indicating that cross-talk between PPARdelta and NF-kappaB is of biological significance in human keratinocytes.Journal of Investigative Dermatology advance online publication, 22 November 2007; doi:10.1038/sj.jid.5701146.
Original languageEnglish
JournalJournal of Investigative Dermatology
Volume128
Issue number5
Pages (from-to)1095-1106
Number of pages11
ISSN0022-202X
DOIs
Publication statusPublished - 2008
Externally publishedYes

Bibliographical note

Keywords: Adult; Cell Differentiation; Cells, Cultured; Epidermis; Histone Deacetylase 1; Histone Deacetylases; Humans; Immunoprecipitation; Keratinocytes; PPAR delta; Protein Structure, Tertiary; Transcription Factor RelA; Transcriptional Activation

ID: 10242594