title: Histamine receptor 2-mediated growth-differentiation factor-15 expression is involved in histamine-induced melanogenesis.
abstract: Vitiligo is a progressive depigmenting disorder. Histamine has been shown to induce melanogenesis via histamine receptor 2, suggesting the possibility of histamine as a repigmenting agent for the treatment of vitiligo. However, the role and signaling mechanism of histamine are still unclear in melanogenesis, especially in relation to growth-differentiation factor-15, which is a protein belonging to transforming growth factor beta and found to be overexpressed in metastatic or malignant melanoma. We found that histamine induces growth-differentiation factor-15 in melanoma cell lines such as SK-MEL-2, B16F10, and melan-a cells. Therefore, in the present study, the role of growth-differentiation factor-15 in histamine-induced melanogenesis was investigated using gene silencing or overexpression of growth-differentiation factor-15 and histamine related compounds such as histamine, amthamine, and cimetidine. Gene silencing of growth-differentiation factor-15 suppressed histamine-induced proliferation, melanin production, tyrosinase activity, and chemotactic migration of SK-MEL-2 cells. Histamine-induced expression of tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2 was also suppressed by growth-differentiation factor-15 gene silencing. On the other hand, overexpression of growth-differentiation factor-15 using a plasmid containing growth-differentiation factor-15 in SK-MEL-2 cells increased melanin production and chemotactic migration. Amthamine induced expression of growth-differentiation factor-15 in a time and concentration dependent manner. Amthamine-induced expression of growth-differentiation factor-15 was suppressed by cimetidine. Our results suggest that growth-differentiation factor-15 is a new player in histamine-induced melanogenesis, which can help researchers to extend the knowledge of the role of the transforming growth factor beta family in melanogenesis and in skin pigment disorders such as vitiligo.
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang 410-820, Republic of Korea.
authors.forename: Hye Ja
authors.initials: HJ
authors.lastname: Lee
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Park
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Lee
authors.forename: You Lee
authors.initials: YL
authors.lastname: Kim
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Kim
authors.forename: Joon Hee
authors.initials: JH
authors.lastname: Kang
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Ai Young
authors.initials: AY
authors.lastname: Lee
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002633:Chemotaxis; D002927:Cimetidine / Q000494:pharmacology; D015870:Gene Expression; D005786:Gene Expression Regulation; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D006632:Histamine / Q000502:physiology*; D017442:Histamine Agonists / Q000494:pharmacology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D017442:Histamine Agonists; D008543:Melanins; D008562:Membrane Glycoproteins; D011970:Receptors, Histamine H2; D013844:Thiazoles; C076207:amthamine; D002927:Cimetidine; D006632:Histamine; D010088:Oxidoreductases; C489799:TYRP1 protein, human; D014442:Monophenol Monooxygenase; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase