title: Latanoprost-induced pigmentation in human iridial melanocytes is fibroblast dependent.
abstract: The prostaglandin F2alpha derivative, latanoprost (LT), used in glaucoma treatment, can induce pigmentation in irises of patients with hazel or heterochromatic eye colour. The mechanism by which LT induces pigmentation in the iris is not yet established, although it does not appear to induce proliferation of iridial melanocytes. The purpose of this study was to develop an in vitro model in which to investigate this mechanism. The pigmentary responses to LT and prostaglandin F(2alpha) (PGF(2alpha)) were examined in human iridial melanocytes alone or in co-culture with epithelial cells (non-ocular human epidermal keratinocytes and iris pigment epithelial cells) or mesenchymal cells (non-ocular dermal fibroblasts or iridial fibroblasts). Melanogenesis was assessed after 4 days culture with prostanoids, using dopa oxidase activity. Prostaglandin FP expression on human iridial fibroblasts and melanocytes was investigated using an immunofluorescent technique employing antibody to PGF(2alpha) receptor and RT-PCR. Iridial melanocytes did not show a convincing increase in dopa oxidase when cultured alone but in the presence of fibroblasts (ocular or non-ocular) there was a significant increase (25-30%) in dopa oxidase activity in response to 10(-7)-10(-5)m LT and PGF(2alpha). Co-culture of melanocytes with epithelial cells, while leading to increased dopa oxidase activity, did not lead to any melanogenic response to LT or PGF(2alpha). FP receptor expression was detected on fibroblasts but not iridial melanocytes by immunocytochemistry and RT-PCR. The melanocyte/fibroblast co-culture model developed in this study also showed that LT and PGF(2alpha) increased dopa oxidase activity in melanocytes from donors with brown but not blue eyes. These results suggest that LT may be inducing pigmentation in the human iris indirectly through the FP receptor on adjacent fibroblasts.
authors.affiliation: Division of Clinical Sciences (North), University Section of Human Metabolism, Northern General Hospital, Sheffield S5 7AU, UK. l.smith-thomas@sheffield.ac.uk
authors.forename: L
authors.initials: L
authors.lastname: Smith-Thomas
authors.forename: M
authors.initials: M
authors.lastname: Moustafa
authors.forename: C S
authors.initials: CS
authors.lastname: Spada
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.forename: R A
authors.initials: RA
authors.lastname: Dawson
authors.forename: M
authors.initials: M
authors.lastname: Wagner
authors.forename: C
authors.initials: C
authors.lastname: Balafa
authors.forename: K M
authors.initials: KM
authors.lastname: Kedzie
authors.forename: J W
authors.initials: JW
authors.lastname: Reagan
authors.forename: A H-P
authors.initials: AH
authors.lastname: Krauss
authors.forename: D F
authors.initials: DF
authors.lastname: Woodward
authors.forename: S
authors.initials: S
authors.lastname: MacNeil
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015237:Dinoprost / Q000494:pharmacology; D005127:Eye Color / Q000187:drug effects* / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000378:metabolism; D000077338:Latanoprost; D008544:Melanocytes / Q000187:drug effects* / Q000201:enzymology; D014442:Monophenol Monooxygenase / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology*; D011982:Receptors, Prostaglandin / Q000378:metabolism; D012867:Skin / Q000166:cytology
chemical_list: D000959:Antihypertensive Agents; D007211:Indoles; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; C009904:melanogen; C034671:prostaglandin F2alpha receptor; D000077338:Latanoprost; D015237:Dinoprost; D014442:Monophenol Monooxygenase