Proteinase-activated receptor-2 stimulates prostaglandin production in keratinocytes: Analysis of prostaglandin receptors on human melanocytes and effects of PGE2 and PGF2α on melanocyte dendricity

Abstract

Prostaglandins (PG) are key mediators of diverse functions in the skin and several reports suggest that PG mediate post-inflammatory pigmentary changes through modulation of melanocyte dendricity and melanin synthesis. The proteinase-activated receptor 2 (PAR-2) is important for skin pigmentation because activation of keratinocyte PAR-2 stimulates uptake of melanosomes through phagocytosis in a Rho-dependent manner. In this report, we show that activation of keratinocyte PAR-2 stimulates release of PGE2 and PGF2α, and that PGE2 and PGF2α, act as paracrine factors that stimulate melanocyte dendricity. We characterized the expression of the EP and FP receptors in human melanocytes and show that human melanocytes express EP1 and EP3, and the FP receptor, but not EP2 and EP4. Treatment of melanocytes with EP1 and EP3 receptor agonists resulted in increased melanocyte dendricity, indicating that both EP1 and EP3 receptor signaling contribute to PGE2-mediated melanocyte dendricity. Certain EP3 receptor subtypes have been shown to increase adenosine 3′,5′- cyclic monophosphate (cAMP) through coupling to Gs, whereas EP1 is known to couple to Gq to activate phospholipase C with elevation in Ca2+. The cAMP/protein kinase A system is known to modulate melanocyte dendrite formation through modulation of Rac and Rho activity. Neither PGF2α, or PGE2 elevated cAMP in human melanocytes showing that dendricity observed in response to PGE2 and PGF2α, is cAMP-independent. Our data suggest that PAR-2 mediates cutaneous pigmentation both through increased uptake of melanosomes by keratinocytes, as well as by release of PGE2 and PGF2α, that stimulate melanocyte dendricity through EP1, EP3, and FP receptors.