PGE2 is a UVR-inducible autocrine factor for human melanocytes that stimulates tyrosinase activation

Prostaglandins activate signalling pathways involved in growth, differentiation and apoptosis. Prostaglandin E-2 (PGE(2)) is released by keratinocytes following ultraviolet irradiation (UVR) and stimulates the formation of dendrites in melanocytes. We show that multiple irradiations of human melanocytes with UVR-activated cPLA(2), the rate-limiting enzyme in eicosanoid synthesis and stimulated PGE(2) secretion. PGE(2) increased cAMP production, tyrosinase activity and proliferation in melanocytes. PGE(2) binds to four distinct G-protein coupled receptors (EP1-4). We show that PGE(2) stimulates EP4 receptor signalling in melanocytes, resulting in cAMP production. Conversely, PGE(2) also stimulated the EP3 receptor in melanocytes, resulting in lowered basal cAMP levels. These data suggest that relative levels or activity of these receptors controls effects of PGE(2) on cAMP in melanocytes. The data are the first to identify PGE(2) as an UVR-inducible autocrine factor for melanocytes. These data also show that PGE(2) activates EP3 and EP4 receptor signalling, resulting in opposing effects on cAMP production, a critical signalling pathway that regulates proliferation and melanogenesis in melanocytes.