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Bee Venom Stimulates Human Melanocyte Proliferation, Melanogenesis, Dendricity and Migration

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Bee Venom Stimulates Human Melanocyte Proliferation, Melanogenesis, Dendricity and Migration EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 39, No.5, 603-613, October 2007 Bee venom stimulates human melanocyte proliferation, melanogenesis, dendricity and migration 1 2 Songhee Jeon *, Nan-Hyung Kim *, migration through PLA2 activation. Overall, in this Byung-Soo Koo3, Hyun-Joo Lee2 and study, we demonstrated that BV may have an effect on Ai-Young Lee1,4 the melanocyte proliferation, melanogenesis, den- dricity and migration through complex signaling path- 1Dongguk University Research Institute of Biotechnology ways in vitro, responsible for the pigmentation. Thus, Medical Science Research Center our study suggests a possibility that BV may be devel- Goyang 410-773, Korea oped as a therapeutic drug for inducing repig- 2Department of Dermatology mentation in vitiligo skin. Dongguk University School of Medicine Goyang 410-773, Korea Keywords: bee venoms; cell movement; cell pro- 3Department of Neuropsychiatry liferation; melanocytes; melanins; skin pigmentation; College of Oriental Medicine vitiligo Dongguk University Goyang 410-773, Korea 4Corresponding author: Tel, 82-31-961-7250; Introduction Fax, 82-31-961-7695; E-mail, [email protected] *These authors contributed equally to this work. Normal human melanocytes are located in the basal layer of the epidermis and rarely undergo mitosis (Jimbow et al., 1975; Pawelek, 1979). It is Accepted 31 July 2007 well accepted that paracrine growth factors pro- Abbreviations: Akt, protein kinase B; CREB, cAMP response duced by keratinocytes, or growth-promoting agents, element binding protein; PI3K, phosphatidylinositol 3-kinase; sPLA2, such as endothelin-1 (ET-1), stem cell factor secreted phospholipase A2 (SCF), basic fibroblast growth factor (bFGF), 12-O- tetradecanoylphorbol 13-acetate (TPA), cAMP- elevating agents (forskolin, IBMX, α-MSH) and Abstract others, regulate melanocyte proliferation along with other diverse melanocyte functions such as Pigmentation may result from melanocyte pro- melanin synthesis and dendricity (Hirobe et al., liferation, melanogenesis, migration or increases in 2004; Imokawa, 2004). The signaling mechanism of each factor in vitro is different. TPA acts on dendricity. Recently, it has been reported that secreted melanocyte growth through activation of PKC (Arita phospholipase A (sPLA ) known as a component of 2 2 et al., 1992), whereas ET-1 and bFGF may affect bee venom (BV), stimulates melanocyte dendricity and melanocyte growth through phosphorylation of pigmentation. BV has been used clinically to control ERK 1/2 (Swope et al., 1995; Tada et al., 2002). rheumatoid arthritis and to ameliorate pain via its an- Activation of ERK1/2 is critical for the mitogenic ti-inflammatory and antinociceptive properties. More- response of melanocytes. Failure to activate this over, after treatment with BV, pigmentation around the kinase is evident in terminally differentiated injection sites was occasionally observed and the pig- melanocytes (Medrano et al., 1994). In human mentation lasted a few months. However, no study has melanocytes, activation of ERK1/2 is sequentially been done about the effect of BV on melanocytes. connected to cAMP response element binding Thus, in the present study, we examined the effect of protein (CREB) activation (Tada et al., 2002). BV on the proliferation, melanogenesis, dendricity and CREB could be a common downstream target for migration in normal human melanocytes and its signal melanocyte differentiation and proliferation. transduction. BV increased the number of melano- Pigmentation may result from melanocyte pro- liferation, melanogenesis, migration (Lan et al., cytes dose and time dependently through PKA, ERK, 2005) or increases in dendricity (Scott et al., 2006). and PI3K/Akt activation. The level of cAMP was also in- Vitiligo is an acquired depigmentation disorder creased by BV treatment. Moreover, BV induced mela- caused by melanocyte death (Kovac, 1998). nogenesis through increased tyrosinase expression. Although more than 1% of the general population Furthermore, BV induced melanocyte dendricity and suffer from vitiligo, recovery of pigmentation is 604 Exp. Mol. Med. Vol. 39(5), 603-613, 2007 often difficult mainly due to the lack of effective Treatment of melanocytes with BV or forskolin methods for treatment. Although several factors, with/without inhibitors including SCF (Grabbe et al., 1994), bFGF Melanocytes from passage numbers between 7 (Halaban et al., 1987), bovine pituitary extract and 15 were used for the experiments. Medium (Wilkins et al., 1985), TPA (Krasagakis et al., 254 with supplements was changed to medium 1993), and cAMP stimulating agents, are known to containing 1/5 the amount of supplements for 24 h induce the proliferation of melanocytes in vitro, before treatment with BV (GUJU Pharma CO., these mitogens are rarely used clinically. Seoul, Korea). To determine the appropriate Recently, it has been reported that secreted concentration of BV, dose-response studies using phospholipase A2 (sPLA2) known as a component various concentrations between 1.25 and 20 µg/ml of bee venom (BV), stimulates melanocyte den- were done. Then, the cells were treated with 10 dricity and pigmentation (Maeda et al., 1996; µg/ml BV or 10 µM forskolin for 1, 3, 5 or 7 days Maeda and Naganuma, 1997; Scott et al., 2006). (Calbiochem, La Jolla, CA). Five cell lines were BV has been used clinically to control rheumatoid examined. arthritis and to ameliorate pain via its anti- For the inhibition experiments, melanocytes inflammatory and antinociceptive properties (Kwon were incubated in the media with 1/5 supplements, et al., 2001). BV also has been shown to have with addition of 2.5 µM U0126, an MEK inhibitor, 1 antibacterial effects (Eiseman et al., 1982; Akdis et µM wortmannin (Calbiochem, La Jolla, CA), a al., 1996; Kwon et al., 2001), and has been used PI3K inhibitor, or 10 µM H89 (Calbiochem, Jolla, as a meridian therapy in Korea (Kim et al., 2003; CA), a PKA inhibitor, for 60 min before BV treat- Lee et al., 2004). Moreover, after treatment with ment. BV, pigmentation around the injection sites was occasionally observed and the pigmentation lasted a few months (unpublished observation), sugge- MTT assay sting that BV may have an effect on the me- The proliferation of melanocytes was examined lanocyte proliferation, melanogenesis, dendricity or using an MTT assay kit (R&D Systems, Minnea- migration responsible for the pigmentation. Thus, polis, MN). Each absorbance was measured at a in the present study, we examined the effect of BV spectrum of 570 nm. The MTT assay was con- on the proliferation, melanogenesis, dendricity and ducted with melanocytes treated with BV in the migration in normal human melanocytes and absence or presence of the above-mentioned elucidated the signaling pathway responsible for stimulators or inhibitors the effect of BV. Measurement of melanin content Materials and Methods The melanin content of cultured melanocytes was measured in accordance with the method des- Normal human epidermal melanocyte culture cribed by Oka et al. (1996). Briefly, the cell pellets o Skin specimens obtained from repeated cesarean were solubilized in boiled 1 M NaOH (80 C) for 2 h. sections and circumcisions were used for cultures. The color was analyzed at a spectrum of 405 nm. Epidermis was separated from dermis after treat- To examine the true melanin formation from the ment with 2.4 U/ml of dispase (Roche, Mannheim, same number of cells, the total melanin content of Germany) for 1 h. The epidermal sheets were each pellet was divided by the number of melano- treated with 0.05% trypsin for 10 min to produce a cytes. suspension of individual epidermal cells. The cells were suspended in Medium 254 (Cascade Biolo- RT-PCR gics, Portland, OR) supplemented with bovine pituitary extract, FBS, bovine insulin, hydrocorti- Total RNA from melanocytes cultured under each sone, bFGF, and bovine transferrin (Cascade condition was isolated using the QuickGene RNA Biologics, Portland, OR), heparin, and PMA (Cas- cultured cell HC kit (Life Science, Minato-ku, cade Biologics, Portland, OR). When the cells Tokyo, Japan). cDNA was synthesized from total reached confluence, they were detached from the RNA using the First Strand cDNA Synthesis Kit for flask and seeded into other culture flasks. RT-PCR (AMV; Boehringer Mannheim, Germany). Human GAPDH was used as the internal standard. The primer sequences of MITF were: forward 5'- ATGCTGGAAATGCTAGAATATAAT-3'; and reverse 5'-ATCATCCATCTGCATACAG-3'; and the primer Effects of bee venom on skin pigmentation 605 sequences of GAPDH were: forward 5'-TCCACTG- Cell migration assay GCGTCTTCACC-3'; and reverse 5'-GGCAGAGA- Cell migration assays were performed as describ- TGATGACCCTTTT-3'. PCR amplification was con- ed previously (Park et al., 2005). Cells were ducted in a 40µl reaction, consisting of 10 × reac- allowed to form a confluent monolayer in a 6-well tion buffer, 2.5 mM MgCl2, 250 µM dNTPs, 100 ng plate. The wound was made by scraping a each PCR primer, 0.5 U Taq DNA polymerase, and conventional pipette tip across the monolayer. The 20-50 ng DNA, using a DNA Thermal Cycler 9600 width of scratch was measured at randomly (Applied Biosystems, Foster city, CA) at 94oC for 1 o o selected 10 areas and the meam value was cal- min, 58 C for 1 min, and 72 C for 1 min at 30 culated. cycles. The DNA fragments produced by PCR were separated by electrophoresis on a 2% agarose gel. Boyden chamber cell migration assay Nucleopore filters with 8 µm pore size (Corning cAMP immunoassay Inc., Corning, NY) were coated with type I colla- gen. The human melanocytes (1 × 104) were Melanocytes were lysed in 0.1 M HCl to inhibit added to the upper chamber and low chambers phosphodiesterase activity and centrifuged at were filled with 10 µg/ml BV with/without PLA2 2,000 g for 15 min. The concentration of cAMP inhibitor. After 72 h of incubation, the filters were was measured using the cAMP assay kit in stained with Hoechst and cells on the upper side of accordance with the manufactures instructions the insert were removed with a cotton swab.
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