Modulation of endothelin-1 in normal human keratinocytes by UVA1/B radiations, prostaglandin E2 and peptidase inhibitors

In the skin, keratinocytes synthesize and secrete endothelin-l (ET-1), a pa tent vasoconstrictor peptide which acts also as a growth factor for most sk in cells. The aim of the study was to test the effects of UVA1 and the asso ciations UVA1/B on the expression of ET-I in normal human keratinocytes and to determine whether exogenously added prostaglandin E2 (PGE2) regulated E T-1 expression. As ET-1 is susceptible to degradation, we also evaluated wh ether ET-I secretion was modulated by peptidase inhibitors. Our results sho wed that UVA1 (365 nm) did not modify the levels of preproET-1 mRNA and pro tein. Moreover, the associations UVA1 + UVB or UVB+UVA1 down-regulated the overexpression of secreted ET-1 induced by UVB alone. PGE2 at 10(-5) M redu ced the expression of ET-I at the mRNA and protein levels but did not exert any significant modification at lower concentrations from 10(-10) to 10(-6 ) M. Phosphoramidon, an endothelin converting enzyme (ECE) inhibitor, drast ically decreased the amount of ET-1 accumulating in the culture medium in b asal conditions or after WE irradiation. Conversely, thiorphan, a specific inhibitor of neutral endopeptidase (NEP), rather increased the levels of ET -1 secretion mainly after UVB irradiation. Taken together, the results show ed that normal human keratinocytes secrete and partly degrade ET-1 through ECE and NEP pathways and pointed out a differential regulation of ET-1 by U VB and UVA1 radiations without any noticeable role for PGE2.