Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibitory mechanism of ginsenoside Rh3 on granulocyte-macrophage colony-stimulating factor expression in UV-B-irradiated murine SP-1 keratinocytes

  • Park, Young Sun (Department of Genetic Engineering & Graduate School of Biotechnology, Kyung Hee University) ;
  • Lee, Ji Eun (Department of Genetic Engineering & Graduate School of Biotechnology, Kyung Hee University) ;
  • Park, Jong Il (Department of Genetic Engineering & Graduate School of Biotechnology, Kyung Hee University) ;
  • Myung, Cheol hwan (Department of Genetic Engineering & Graduate School of Biotechnology, Kyung Hee University) ;
  • Lim, Young-Ho (KGC R&D Headquarters) ;
  • Park, Chae Kyu (KGC R&D Headquarters) ;
  • Hwang, Jae Sung (Department of Genetic Engineering & Graduate School of Biotechnology, Kyung Hee University)
  • Received : 2018.07.26
  • Accepted : 2018.12.18
  • Published : 2020.03.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Ultraviolet (UV) goes through the epidermis and promotes release of inflammatory cytokines in keratinocytes. Granulocyte-macrophage colony-stimulating factor (GM-CSF), one of the keratinocyte-derived cytokines, regulates proliferation and differentiation of melanocytes. Extracellular signal-regulated kinase (ERK1/2) and protein kinase C (PKC) signaling pathways regulate expression of GM-CSF. Based on these results, we found that ginsenoside Rh3 prevented GM-CSF production and release in UV-B-exposed SP-1 keratinocytes and that this inhibitory effect resulted from the reduction of PKCδ and ERK phosphorylation. Methods: We investigated the mechanism by which ginsenoside Rh3 from Panax ginseng inhibited GM-CSF release from UV-B-irradiated keratinocytes. Results: Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) or UV-B induced release of GM-CSF in the SP-1 keratinocytes. To elucidate whether the change in GM-CSF expression could be related to PKC signaling, the cells were pretreated with H7, an inhibitor of PKC, and irradiated with UV-B. GM-CSF was decreased by H7 in a dose-dependent manner. When we analyzed which ginsenosides repressed GM-CSF expression among 15 ginsenosides, ginsenoside Rh3 showed the largest decline to 40% of GM-CSF expression in enzyme-linked immunosorbent assay. Western blot analysis showed that TPA enhanced the phosphorylation of PKCδ and ERK in the keratinocytes. When we examined the effect of ginsenoside Rh3, we identified that ginsenoside Rh3 inhibited the TPA-induced phosphorylation levels of PKCδ and ERK. Conclusion: In summary, we found that ginsenoside Rh3 impeded UV-B-induced GM-CSF production through repression of PKCδ and ERK phosphorylation in SP-1 keratinocytes.

Keywords

References

  1. Li M, Chiba H, Warot X, Messaddeq N, Gerard C, Chambon P, Metzger D. RXRalpha ablation in skin keratinocytes results in alopecia and epidermal alterations. Development 2001;128:675-88. https://doi.org/10.1242/dev.128.5.675
  2. Hirobe T. Role of keratinocyte-derived factors involved in regulating the proliferation and differentiation of mammalian epidermal melanocytes. Pigm Cell Res 2005;18:2-12. https://doi.org/10.1111/j.1600-0749.2004.00198.x
  3. Prota G. Pigment cell research: what directions? Pigm Cell Res 1997;10:5-11. https://doi.org/10.1111/j.1600-0749.1997.tb00460.x
  4. Lee EJ, Jeon MS, Kim BD, Kim JH, Kwon YG, Lee H, Lee YS, Yang JH, Kim TY. Capsiate inhibits ultraviolet B-induced skin inflammation by inhibiting Src family kinases and epidermal growth factor receptor signaling. Free Radic Biol Med 2010;48:1133-43. https://doi.org/10.1016/j.freeradbiomed.2010.01.034
  5. Hirobe T, Furuya R, Hara E, Horii I, Tsunenaga M, Ifuku O. Granulocytemacrophage colony-stimulating factor (GM-CSF) controls the proliferation and differentiation of mouse epidermal melanocytes from pigmented spots induced by ultraviolet radiation B. Pigm Cell Res 2004;17:230-40. https://doi.org/10.1111/j.1600-0749.2004.00132.x
  6. Reibman J, Talbot AT, Hsu Y, Ou G, Jover J, Nilsen D, Pillinger MH. Regulation of expression of granulocyte-macrophage colony-stimulating factor in human bronchial epithelial cells: roles of protein kinase C and mitogen-activated protein kinases. J Immunol 2000;165:1618-25. https://doi.org/10.4049/jimmunol.165.3.1618
  7. Gilchrest BA, Park HY, Eller MS, Yaar M. Mechanisms of ultraviolet lightinduced pigmentation. Photochem Photobiol 1996;63:1-10. https://doi.org/10.1111/j.1751-1097.1996.tb02988.x
  8. Liu JF, Crepin M, Liu JM, Barritault D, Ledoux D. FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway. Biochem Biophys Res Commun 2002;293:1174-82. https://doi.org/10.1016/S0006-291X(02)00350-9
  9. Brodie C, Blumberg P. Regulation of cell apoptosis by protein kinase c ${\delta}$. Apoptosis 2003;8:19-27. https://doi.org/10.1023/A:1021640817208
  10. Chen N, Ma W-y, Huang C, Dong Z. Translocation of protein kinase $C{\varepsilon}$ and protein kinase $C{\delta}$ to membrane is required for ultraviolet B-induced activation of mitogen-activated protein kinases and apoptosis. J Biol Chem 1999;274:15389-94. https://doi.org/10.1074/jbc.274.22.15389
  11. Aziz MH, Manoharan HT, Verma AK. Protein kinase Cε, which sensitizes skin to sun's UV radiationeinduced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res 2007;67:1385-94. https://doi.org/10.1158/0008-5472.CAN-06-3350
  12. Oh CT, Park JI, Jung YR, Joo YA, Shin DH, Cho HJ, Ahn SM, Lim Y-H, Park CK, Hwang JS. Inhibitory effect of Korean Red Ginseng on melanocyte proliferation and its possible implication in GM-CSF mediated signaling. J Ginseng Res 2013;37:389. https://doi.org/10.5142/jgr.2013.37.389
  13. Attele AS, Wu JA, Yuan C-S. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58:1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  14. Yayeh T, Jung K-H, Jeong HY, Park J-H, Song Y-B, Kwak Y-S, Kang H-S, Cho JY, Oh J-W, Kim S-K. Korean red ginseng saponin fraction downregulates proinflammatory mediators in LPS stimulated RAW264. 7 cells and protects mice against endotoxic shock. J Ginseng Res 2012;36:263. https://doi.org/10.5142/jgr.2012.36.3.263
  15. Sies H, Stahl W. Nutritional protection against skin damage from sunlight. Annu Rev Nutr 2004;24:173-200. https://doi.org/10.1146/annurev.nutr.24.012003.132320
  16. Kock A, Schwarz T, Kirnbauer R, Urbanski A, Perry P, Ansel J, Luger T. Human keratinocytes are a source for tumor necrosis factor alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light. J Exp Med 1990;172:1609-14. https://doi.org/10.1084/jem.172.6.1609
  17. Yamaguchi Y, Hearing VJ. Physiological factors that regulate skin pigmentation. Biofactors 2009;35:193-9. https://doi.org/10.1002/biof.29
  18. Chung I, Lee J, Park YS, Lim Y, Chang DH, Park J, Hwang JS. Inhibitory mechanism of Korean red ginseng on GM-CSF expression in UVB-irradiated keratinocytes. J Ginseng Res 2015;39:322-30. https://doi.org/10.1016/j.jgr.2015.03.001
  19. Shin Y, Bae E, Kim D. Inhibitory effect of ginsenoside Rg5 and its metabolite ginsenoside Rh3 in an oxazolone-induced mouse chronic dermatitis model. Arch Pharm Res 2006;29:685-90. https://doi.org/10.1007/BF02968253
  20. Lee YY, Park J, Lee E, Lee S, Kim D, Kang JL, Kim H. Anti-inflammatory mechanism of ginseng saponin metabolite Rh3 in lipopolysaccharidestimulated microglia: critical role of 5'-adenosine monophosphateactivated protein kinase signaling pathway. J Agric Food Chem 2015;63:3472-80. https://doi.org/10.1021/jf506110y
  21. Park J, Park E, Kim D, Jung K, Jung J, Lee E, Hyun J, Kang JL, Kim H. Anti-inflammatory mechanism of ginseng saponins in activated microglia. J Neuroimmunol 2009;209:40-9. https://doi.org/10.1016/j.jneuroim.2009.01.020
  22. Rivedal E, Opsahl H. Role of PKC and MAP kinase in EGF-and TPA-induced connexin43 phosphorylation and inhibition of gap junction intercellular communication in rat liver epithelial cells. Carcinogenesis 2001;22:1543-50. https://doi.org/10.1093/carcin/22.9.1543
  23. Siflinger-Birnboim A, Goligorsky M, Del Vecchio P, Malik A. Activation of protein kinase C pathway contributes to hydrogen peroxide-induced increase in endothelial permeability. Lab Invest: J Tech Methods Pathol 1992;67:24-30.
  24. Denning MF, Wang Y, Nickoloff BJ, Wrone-Smith T. Protein kinase $C{\delta}$ is activated by caspase-dependent proteolysis during ultraviolet radiation-induced apoptosis of human keratinocytes. J Biol Chem 1998;273:29995-30002. https://doi.org/10.1074/jbc.273.45.29995
  25. Bode AM, Dong Z. Mitogen-activated protein kinase activation in UV-induced signal transduction. Sci Signal 2003;2003:re2. https://doi.org/10.1126/stke.2003.167.re2
  26. Jirousek MR, Goekjian PG. Protein kinase C inhibitors as novel anticancer drugs. Expert Opin Investig Drugs 2001;10:2117-40. https://doi.org/10.1517/13543784.10.12.2117
  27. Ueda Y, Hirai S-i, Osada S-i, Suzuki A, Mizuno K, Ohno S. Protein kinase $C{\delta}$ activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf. J Biol Chem 1996;271:23512-9. https://doi.org/10.1074/jbc.271.38.23512
  28. Esnault S, Malter JS. Hyaluronic acid or TNF-a plus fibronectin triggers granulocyte macrophage-colony-stimulating factor mRNA stabilization in eosinophils yet engages differential intracellular pathways and mRNA binding proteins. J Immunol 2003;171:6780-7. https://doi.org/10.4049/jimmunol.171.12.6780
  29. Kawada A, Hiruma M, Noguchi H, Ishibashi A, Motoyoshi K, Kawada I. Granulocyte and macrophage colony-stimulating factors stimulate proliferation of human keratinocytes. Arch Dermatol Res 1997;289:600-2. https://doi.org/10.1007/s004030050246
  30. Braunstein S, Kaplan G, Gottlieb AB, Schwartz M, Walsh G, Abalos RM, Fajardo TT, Guido LS, Krueger JG. GM-CSF activates regenerative epidermal growth and stimulates keratinocyte proliferation in human skin in vivo. J Invest Dermatol 1994;103(4).
  31. Mondrinos MJ, Zhang T, Sun S, Kennedy PA, King DJ, Wolfson MR, Knight LC, Scalia R, Kilpatrick LE. Pulmonary endothelial protein kinase C-delta (PKCd) regulates neutrophil migration in acute lung inflammation. Am J Pathol 2014;184:200-13. https://doi.org/10.1016/j.ajpath.2013.09.010
  32. Hamdorf M, Berger A, Schule S, Reinhardt J, Flory E. $PKC{\delta}$-Induced PU. 1 phosphorylation promotes hematopoietic stem cell differentiation to dendritic cells. Stem Cells 2011;29:297-306. https://doi.org/10.1002/stem.564
  33. Page K, Li J, Zhou L, Iasvoyskaia S, Corbit KC, Soh J, Weinstein IB, Brasier AR, Lin A, Hershenson MB. Regulation of airway epithelial cell NF-kB-dependent gene expression by protein kinase $c{\delta}$. J Immunol 2003;170:5681-9. https://doi.org/10.4049/jimmunol.170.11.5681
  34. Morgan S, Yamanouchi D, Harberg C, Wang Q, Keller M, Si Y, Burlingham W, Seedial S, Lengfeld J, Liu B. Elevated protein kinase C-${\delta}$ contributes to aneurysm pathogenesis through stimulation of apoptosis and inflammatory signaling. Arterioscler Thromb Vasc Biol 2012;32:2493-502. https://doi.org/10.1161/ATVBAHA.112.255661
  35. Mayr M, Chung Y, Mayr U, McGregor E, Troy H, Baier G, Leitges M, Dunn MJ, Griffiths JR, Xu Q. Loss of PKC-${\delta}$ alters cardiac metabolism. Am J Physiol Heart Circ Physiol 2004;287:H945.
  36. Kokorovic A, Cheung GW, Breen DM, Chari M, Lam CK, Lam TK. Duodenal mucosal protein kinase C-${\delta}$ regulates glucose production in rats. Gastroenterology 2011;141:1720-7. https://doi.org/10.1053/j.gastro.2011.06.042
  37. Jin H, Kanthasamy A, Harischandra DS, Kondru N, Ghosh A, Panicker N, Anantharam V, Rana A, Kanthasamy AG. Histone hyperacetylation upregulates $PKC{\delta}$ in dopaminergic neurons to induce cell death: relevance to epigenetic mechanisms of neurodegeneration in Parkinson's disease. J Biol Chem 2014. jbc. M114. 576702.
  38. Lim K, Kwon J, Kim K, Noh J, Kang S, Park J, Lee M, Bae O, Chung J. Emodin inhibits tonic tension through suppressing $PKC{\delta}$-mediated inhibition of myosin phosphatase in rat isolated thoracic aorta. Br J Pharmacol 2014;171:4300-10. https://doi.org/10.1111/bph.12804
  39. Lee JE, Park JI, Myung CH, Hwang JS. Inhibitory effects of ginsenosides on basic fibroblast growth factor-induced melanocyte proliferation. J Ginseng Res 2017;41:268-76. https://doi.org/10.1016/j.jgr.2016.05.001
  40. Oh J, Chun K, Joo S, Oh Y, Lee S. Caspase-3-dependent protein kinase C delta activity is required for the progression of ginsenoside-Rh2-induced apoptosis in SK-HEP-1 cells. Cancer Lett 2005;230:228-38. https://doi.org/10.1016/j.canlet.2004.12.043
  41. Nam Y, Wie MB, Shin E, Nguyen TL, Nah S, Ko SK, Jeong JH, Jang C, Kim H. Ginsenoside re protects methamphetamine-induced mitochondrial burdens and proapoptosis via genetic inhibition of protein kinase C ${\delta}$ in human neuroblastoma dopaminergic SH-SY5Y cell lines. J Appl Toxicol 2015;35:927-44. https://doi.org/10.1002/jat.3093
  42. Lee H-G, Yang J-H. PKC-${\delta}$ mediates TCDD-induced apoptosis of chondrocyte in ROS-dependent manner. Chemosphere 2010;81:1039-44. https://doi.org/10.1016/j.chemosphere.2010.08.045
  43. Makino J, Kamiya T, Hara H, Adachi T. TPA induces the expression of EC-SOD in human monocytic THP-1 cells: involvement of PKC, MEK/ERK and NOXderived ROS. Free Radical Res 2012;46:637-44. https://doi.org/10.3109/10715762.2012.664841

Cited by

  1. Improving NKCC1 Function Increases the Excitability of DRG Neurons Exacerbating Pain Induced After TRPV1 Activation of Primary Sensory Neurons vol.15, 2020, https://doi.org/10.3389/fncel.2021.665596
  2. The regulatory role of Korean ginseng in skin cells vol.45, pp.3, 2020, https://doi.org/10.1016/j.jgr.2020.08.004
  3. Protective Effect of Potentilla glabra in UVB-Induced Photoaging Process vol.26, pp.17, 2021, https://doi.org/10.3390/molecules26175408
  4. Determination of ginsenoside Rh3 in rat plasma by LC–MS/MS and its application to a pharmacokinetic study vol.36, pp.2, 2020, https://doi.org/10.1002/bmc.5268