Vitamin D Induces Cyclooxygenase 2 Dependent Prostaglandin E₂ Synthesis in HaCaT Keratinocytes

Abstract

The active metabolite of vitamin D calcitriol and its analogs are well-known for their anti-inflammatory action in the skin, while their main side effect associated with topical treatment of inflammatory disorders is irritant contact dermatitis. Prostaglandin E2 (PGE2 ) is pro-inflammatory at the onset of inflammation and anti-inflammatory at its resolution. We hypothesized that induction of PGE2 synthesis by calcitriol in epidermal keratinocytes may contribute both to its pro-inflammatory and anti-inflammatory effects on the skin. Treatment of human immortalized HaCaT keratinocytes with calcitriol (3-100 nM, 2-24 h) increased PGE2 production due to increased mRNA and protein expression of COX-2, but not to increase of COX-1 or release of arachidonic acid. The effect of calcitriol on COX-2 mRNA was observed also in primary human keratinocytes. The increase in COX-2 mRNA is associated with COX-2 transcript stabilization. Calcitriol exerts this effect by a rapid (2 h) and protein synthesis independent mode of action that is dependent on PKC and Src kinase activities. Treatment with a COX-2 inhibitor partially prevented the attenuation of the keratinocyte inflammatory response by calcitriol. We conclude that upregulation of COX-2 expression with the consequent increase in PGE2 synthesis may be one of the mechanisms explaining the Janus face of calcitriol as both a promoter and attenuator of cutaneous inflammation. J. Cell. Physiol. 231: 837-843, 2016. © 2015 Wiley Periodicals, Inc.

cPLA2α Enzyme Inhibition Attenuates Inflammation and Keratinocyte Proliferation

“…In AVX001-treated cells, calcipotriol was unable to stimulate PGE 2 release, implicating that cPLA2α activation is required. This is in contrast to studies in keratinocytes by Ravid et al [ 55 ], who suggest that the upregulation of COX-2 as opposed to increased AA production is responsible for the stimulation of PGE 2 production. Doroudi et al [ 74 ] present a VDR-independent mechanism for activation of cPLA 2 α by calcitriol via Ca 2+ /calmodulin-dependent protein kinase II (CAMKII)-dependent phosphorylation.…”

“…Calcipotriol is a topical therapeutic for psoriasis and is known to cause skin irritation [ 54 ]. We demonstrate that calcipotriol stimulates the release of PGE 2 both in PBMC and keratinocytes, which is in agreement with the following studies [ 55 , 56 , 73 ] and further supports the involvement of VDR/PGE 2 signaling in drug-induced skin toxicity, as proposed by Shah et al [ 56 ]. The mechanism by which calcipotriol stimulates PGE 2 production is unclear.…”

“…Skin toxicity is a common side-effect of a variety of drug types including the vitamin D receptor (VDR) agonist calcitriol and its analogue calcipotriol, both of which are used to treat psoriasis [ 54 ]. The pro-inflammatory effects of VDR agonists are suggested to involve PGE 2 [ 55 , 56 ]. To investigate the role of cPLA 2 α in VDR agonist-mediated PGE 2 release, we treated PBMC and HaCaT with calcipotriol in the absence or presence of AVX001.…”

Tissue-specific contributions of Tmem79 to atopic dermatitis and mast cell-mediated histaminergic itch

“…Do keratinocytes in the epidermis constitute a source of PGE 2 in Tmem79 −/− mice (20,21,23)? Indeed, we observed a specific increase in PGE 2 , but not in the prostanoid precursor PGH 2 (SI Appendix, Fig.…”

Down-regulation of COX-2 activity by 1α,25(OH)2D3 is VDR dependent in endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor

“…There are many reports showing the anti-inflammatory action of 1α,25(OH) 2 D 3 through the inhibition of COX-2 expression [ 20 , 35 , 36 ]. On the other hand, some data demonstrated vitamin D induces COX-2 expression in epithelial cells [ 37 , 38 ] Therefore Cox- 2 mRNA levels were evaluated by qRT-PCR at different time points (0.3–48 h) after 1α,25(OH) 2 D 3 (10 nM) or vehicle (0.01% ethanol) treatments in presence of DMEM 2% FBS. Results presented in Figure 2 A show an increased expression of Cox- 2 mRNA induced by 1α,25(OH) 2 D 3 .…”