The possible separation of 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation and hyperplasia by compound A

Piotr Kowalczyk, Magdalena C. Kowalczyk, Jacob J. Junco, Olga Tolstykh, Tatsuya Kinjo, Ha Truong, Zbigniew Walaszek, Margaret Hanausek, Thomas J. Slaga

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Activated glucocorticoid receptor (GR) acts via two different mechanisms: transcriptional regulation that requires DNA-binding, and protein-protein interaction between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1). It has been postulated that many important effects of glucocorticoids, including their anti-inflammatory properties, depend on GR's transrepressive effects on NF-κB and AP-1. In the present study, we have employed a TPA-induced model of skin inflammation and epidermal hyperplasia to determine whether partial activation of the glucocorticoid receptor by compound A (CpdA) is sufficient to reverse the effect of TPA treatment. CpdA is a nonsteroidal GR modulator with high binding affinity, is capable of partial activation of GR. Topical application of TPA twice per week for 2wk results in inflammation and epidermal hyperplasia. TPA treatment also elevates levels of c-jun (AP-1 component), cyclooxygenase-2 (COX-2), p50 (NF-κB component), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in the skin. Fluocinolone acetonide (FA) (a full GR agonist) was able to completely reverse the above effects of TPA. When applied alone, CpdA increased the epidermal thickness and keratinocyte proliferation as well as levels of c-jun, COX-2, IL-6, and IFN-γ. However, CpdA treatment resulted in a decrease in the number of p50 positive cells induced by TPA, suggesting its role in inhibition of NF-κB. The level of metallothionein-1 mRNA, regulated by GR was also significantly decreased in skin samples treated with CpdA. Our results suggest that CpdA is able to inhibit GR transactivation and activate only some transrepression properties of GR.

Original languageEnglish (US)
Pages (from-to)488-496
Number of pages9
JournalMolecular Carcinogenesis
Volume52
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Dissociated glucocorticoids
  • Glucocorticoid receptor
  • SENCAR mice

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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