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

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 two weeks 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.

Emptying of Intracellular Calcium Pool and Oxidative Stress Imbalance Are Associated with the Glyphosate-Induced Proliferation in Human Skin Keratinocytes HaCaT Cells

“…The results of the present study showed a significant increase in two Ca 2+ binding proteins, S100A6, and S100A9 (Figure 6(a)). In the past, we studied alterations in global protein expression using samples of mouse skin treated with glyphosate and the tumor promoter TPA, which is a potent activator of keratinocyte proliferation [46], epidermal hyperplasia and dermal inflammation [47], and we found strong upregulation of S100A6 and S100A9 [30]. More recently, strong upregulation of both proteins was also reported by us in HaCaT cells upon mancozeb (fungicide) exposure [48].…”

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

“…The effect of CpdA was also examined on a 12-Otetradecanoylphorbol-13-acetate (TPA)-induced model of skin inflammation and hyperplasia in which it was shown that CpdA's ability to reverse this induction was less explicit compared to a classical GC. However, an increase in epidermal thickness and keratinocyte proliferation was observed after CpdA-treatment in a dose-dependent manner (Kowalczyk et al, 2013). It still needs to be investigated what the effect is of other SEGRMs, such as AL-438, PF-802, Org-214007-0 and LGD-5552 on muscle and skin metabolism.…”

“…A number of research lines have focused on topical skin and eye preparations (Schacke et al, 2009;Zhang et al, 2009;Kowalczyk et al, 2013;Baiula et al, 2014;Spinelli et al, 2014;USNIH, 2014d,g,h,j,o,p). Nevertheless, additional research into tissue-specific delivery systems for these pharmacological compounds would aid in reducing the remaining side effects even more.…”

Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin

“…The studies of topical CpdA effects in skin have been limited, and yielded controversial results. 5 , 32 In addition, the effects of CpdA on GR activity in keratinocytes have not been investigated. As effect of GR ligands on gene expression strongly depends on the cell type, 12 , 33 , 34 in the presented work, we assessed CpdA effects on gene expression in keratinocytes in vitro and in vivo.…”