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Korean Red Ginseng improves atopic dermatitis-like skin lesions by suppressing expression of proinflammatory cytokines and chemokines in vivo and in vitro

  • Kee, Ji-Ye (Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University) ;
  • Jeon, Yong-Deok (Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University) ;
  • Kim, Dae-Seung (Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University) ;
  • Han, Yo-Han (Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University) ;
  • Park, Jinbong (College of Korean Medicine, Institute of Korean Medicine, Kyung Hee University) ;
  • Youn, Dong-Hyun (College of Korean Medicine, Institute of Korean Medicine, Kyung Hee University) ;
  • Kim, Su-Jin (Department of Cosmeceutical Science, Daegu Hanny University) ;
  • Ahn, Kwang Seok (College of Korean Medicine, Institute of Korean Medicine, Kyung Hee University) ;
  • Um, Jae-Young (College of Korean Medicine, Institute of Korean Medicine, Kyung Hee University) ;
  • Hong, Seung-Heon (Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University)
  • Received : 2015.10.14
  • Accepted : 2016.02.09
  • Published : 2017.04.15

Abstract

Background: The prevalence of allergic inflammatory diseases such as atopic dermatitis (AD), asthma, and allergic rhinitis worldwide has increased and complete recovery is difficult. Korean Red Ginseng, which is the heat-processed root of Panax ginseng Meyer, is widely and frequently used as a traditional medicine in East Asia. In this study, we investigated whether Korean Red Ginseng water extract (RGE) regulates the expression of proinflammatory cytokines and chemokines via the mitogen-activated protein kinases (MAPKs)/nuclear factor kappa B ($NF-{\kappa}B$) pathway in allergic inflammation. Methods: Compound 48/80-induced anaphylactic shock and 1-fluoro-2,4-dinitrobenzene (DNFB)-induced AD-like skin lesion mice models were used to investigate the antiallergic effects of RGE. Human keratinocytes (HaCaT cells) and human mast cells (HMC-1) were also used to clarify the effects of RGE on the expression of proinflammatory cytokines and chemokines. Results: Anaphylactic shock and DNFB-induced AD-like skin lesions were attenuated by RGE administration through reduction of serum immunoglobulin E (IgE) and interleukin (IL)-6 levels in mouse models. RGE also reduced the production of proinflammatory cytokines including $IL-1{\beta}$, IL-6, and IL-8, and expression of chemokines such as IL-8, thymus and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) in HaCaT cells. Additionally, RGE decreased the release of tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), $IL-1{\beta}$, IL-6, and IL-8 as well as expressions of chemokines including macro-phage inflammatory protein $(MIP)-1{\alpha}$, $MIP-1{\beta}$, regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, and IL-8 in HMC-1 cells. Furthermore, our data demonstrated that these inhibitory effects occurred through blockage of the MAPK and $NF-{\kappa}B$ pathway. Conclusion: RGE may be a useful therapeutic agent for the treatment of allergic inflammatory diseases such as AD-like dermatitis.

Keywords

References

  1. Leung DYM, Bieber T. Atopic dermatitis. Lancet 2003;361:151-60. https://doi.org/10.1016/S0140-6736(03)12193-9
  2. Novak N. New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy 2009;64:265-75. https://doi.org/10.1111/j.1398-9995.2008.01922.x
  3. Sebastiani S, Albanesi C, De PO, Puddu P, Cavani A, Girolomoni G. The role of chemokines in allergic contact dermatitis. Arch Dermatol Res 2002;293:552-9. https://doi.org/10.1007/s00403-001-0276-9
  4. Grone A. Keratinocytes and cytokines. Vet Immunol Immunopathol 2002;88:1-12. https://doi.org/10.1016/S0165-2427(02)00136-8
  5. Uchi H, Terao H, Koga T, Furue M. Cytokines and chemokines in the epidermis. J Dermatol Sci 2000;24(Suppl. 1):S29-38. https://doi.org/10.1016/S0923-1811(00)00138-9
  6. Barker JN, Jones ML, Mitra RS, Crockett-Torabe E, Fantone JC, Kunkel SL, Warren JS, Dixit VM, Nickoloff BJ. Modulation of keratinocyte-derived interleukin-8 which is chemotactic for neutrophils and T lymphocytes. Am J Pathol 1991;139:869-76.
  7. Horikawa T, Nakayama T, Hikita I, Yamada H, Fujisawa R, Bito T, Harada S, Fukunaga A, Chantry D, Gray PW, et al. IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis. Int Immunol 2002;14:767-73. https://doi.org/10.1093/intimm/dxf044
  8. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as ”tunable“ effector and immunoregulatory cells: recent advances. Annu Rev Immunol 2005;23:749-86. https://doi.org/10.1146/annurev.immunol.21.120601.141025
  9. Kawakami T, Ando T, Kimura M, Wilson BS, Kawakami Y. Mast cells in atopic dermatitis. Curr Opin Immunol 2009;21:666-78. https://doi.org/10.1016/j.coi.2009.09.006
  10. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B, Asadi S, Vasiadi M, Weng Z, Miniati A, et al. Mast cells and inflammation. Biochim Biophys Acta 2012;1822:21-33. https://doi.org/10.1016/j.bbadis.2010.12.014
  11. Galli SJ, Tsai M. Mast cells in allergy and infection: versatile effector and regulatory cells in innate and adaptive immunity. Eur J Immunol 2010;40:1843-51. https://doi.org/10.1002/eji.201040559
  12. Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 2002;298:1911-2. https://doi.org/10.1126/science.1072682
  13. Hommes DW, Peppelenbosch MP, van Deventer SJ. Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti-inflammatory targets. Gut 2003;52:144-51. https://doi.org/10.1136/gut.52.1.144
  14. May MJ, Ghosh S. Signal transduction through NF-kappa B. Immunol Today 1998;19:80-8. https://doi.org/10.1016/S0167-5699(97)01197-3
  15. Arthur JS, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 2013;13:679-92. https://doi.org/10.1038/nri3495
  16. Finco TS, Baldwin AS. Mechanistic aspects of NF-kappa B regulation: the emerging role of phosphorylation and proteolysis. Immunity 1995;3:263-72. https://doi.org/10.1016/1074-7613(95)90112-4
  17. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066-71. https://doi.org/10.1056/NEJM199704103361506
  18. Barnes PJ. Pathophysiology of allergic inflammation. Immunol Rev 2011;242:31-50. https://doi.org/10.1111/j.1600-065X.2011.01020.x
  19. Choi J, Kim TH, Choi TY, Lee MS. Ginseng for health care: a systematic review of randomized controlled trials in Korean literature. PLoS ONE 2013;8:e59978. https://doi.org/10.1371/journal.pone.0059978
  20. Heo JH, Lee ST, Oh MJ, Park HJ, Shim JY, Chu K, Kim M. Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with Korean Red Ginseng. J Ginseng Res 2011;35:457-61. https://doi.org/10.5142/jgr.2011.35.4.457
  21. Park JB, Kwon SK, Nagar H, Jung SB, Jeon BH, Kim CS, Oh JH, Song HJ, Kim CS. Rg3-enriched Korean Red Ginseng improves vascular function in spontaneously hypertensive rats. J Ginseng Res 2014;38:244-50. https://doi.org/10.1016/j.jgr.2014.05.011
  22. Jung JH, Kang IG, Kim DY, Hwang YJ, Kim ST. The effect of Korean Red Ginseng on allergic inflammation in a murine model of allergic rhinitis. J Ginseng Res 2013;37:167-75. https://doi.org/10.5142/jgr.2013.37.167
  23. Lee EJ, Song MJ, Kwon HS, Ji GE, Sung MK. Oral administration of fermented red ginseng suppressed ovalbumin-induced allergic responses in female BALB/c mice. Phytomedicine 2012;19:896-903. https://doi.org/10.1016/j.phymed.2012.04.008
  24. Im EJ, Yayeh T, Park SJ, Kim SH, Goo YK, Hong SB, Son YM, Kim SD, Rhee MH. Antiatherosclerotic effect of Korean Red Ginseng extract involves regulator of g-protein signaling 5. Evid Based Complement Alternat Med 2014;2014:985174.
  25. Han JY, Ahn SY, Oh EH, Nam SY, Hong JT, Oh KW, Lee MK. Red ginseng extract attenuates kainate-induced excitotoxicity by antioxidative effects. Evid Based Complement Alternat Med 2012;2012:479016.
  26. Jhun J, Lee J, Byun JK, Kim EK, Woo JW, Lee JH, Kwok SK, Ju JH, Park KS, Kim HY, et al. Red ginseng extract ameliorates autoimmune arthritis via regulation of STAT3 pathway, Th17/Treg balance, and osteoclastogenesis in mice and human. Mediators Inflamm 2014;2014:351856.
  27. Kim SJ, Kee JY, Choi IY, Kim MC, Kim DS, Jeon YD, Kim SG, Kim BS, Jung HJ, Kim HM, et al. Insamhodo-tang, a traditional Korean medicine, regulates mast cell-mediated allergic inflammation in vivo and in vitro. J Ethnopharmacol 2011;134:339-47. https://doi.org/10.1016/j.jep.2010.12.023
  28. Albanesi C. Keratinocytes in allergic skin diseases. Curr Opin Allergy Clin Immunol 2010;10:452-6. https://doi.org/10.1097/ACI.0b013e32833e08ae
  29. Ko HM, Joo SH, Kim P, Park JH, Kim HJ, Bahn GH, Kim HY, Lee J, Han SH, Shin CY, et al. Effects of Korean Red Ginseng extract on tissue plasminogen activator and plasminogen activator inhibitor-1 expression in cultured rat primary astrocytes. J Ginseng Res 2013;37:401-12. https://doi.org/10.5142/jgr.2013.37.401
  30. Im GJ, Chang JW, Choi J, Chae SW, Ko EJ, Jung HH. Protective effect of Korean Red Ginseng extract on cisplatin ototoxicity in HEI-OC1 auditory cells. Phytother Res 2010;24:614-21.
  31. Mitev V, Miteva L. Signal transduction in keratinocytes. Exp Dermatol 1999;8:96-108. https://doi.org/10.1111/j.1600-0625.1999.tb00355.x
  32. Duan W, Wong WS. Targeting mitogen-activated protein kinases for asthma. Curr Drug Targets 2006;7:691-8. https://doi.org/10.2174/138945006777435353
  33. Lee JH, Cho SH. Korean Red Ginseng extract ameliorates skin lesions in NC/Nga mice: an atopic dermatitis model. J Ethnopharmacol 2011;133:810-7. https://doi.org/10.1016/j.jep.2010.11.020
  34. Cho E, Cho SH. Effects of Korean Red Ginseng extract on the prevention of atopic dermatitis and its mechanism on early lesions in a murine model. J Ethnopharmacol 2013;145:294-302. https://doi.org/10.1016/j.jep.2012.11.006
  35. Sohn EH, Jang SA, Lee CH, Jang KH, Kang SC, Park HJ, Pyo S. Effects of Korean Red Ginseng extract for the treatment of atopic dermatitis-like skin lesions in mice. J Ginseng Res 2011;35:479-86. https://doi.org/10.5142/jgr.2011.35.4.479
  36. Pease JE, Williams TJ. Chemokines and their receptors in allergic disease. J Allergy Clin Immunol 2006;118:305-18. https://doi.org/10.1016/j.jaci.2006.06.010
  37. Saeki H, Tamaki K. Thymus and activation regulated chemokine (TARC)/CCL17 and skin diseases. J Dermatol Sci 2006;43:75-84. https://doi.org/10.1016/j.jdermsci.2006.06.002
  38. Kimata H, Lindley I. Detection of plasma interleukin-8 in atopic dermatitis. Arch Dis Child 1994;70:119-22. https://doi.org/10.1136/adc.70.2.119
  39. Jahnz-Rozyk K, Targowski T, Paluchowska E, Owczarek W, Kucharczyk A. Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis. Allergy 2005;60:685-8. https://doi.org/10.1111/j.1398-9995.2005.00774.x
  40. Shimada Y, Takehara K, Sato S. Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis. J Dermatol Sci 2004;34:201-8. https://doi.org/10.1016/j.jdermsci.2004.01.001
  41. Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A, Fusenig NE. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol 1988;106:761-71. https://doi.org/10.1083/jcb.106.3.761
  42. Pastore S, Lulli D, Potapovich AI, Fidanza P, Kostyuk VA, Dellambra E, De Luca C, Maurelli R, Korkina LG. Differential modulation of stress-inflammation responses by plant polyphenols in cultured Normal human keratinocytes and immortalized HaCaT cells. J Dermatol Sci 2011;63:104-14.
  43. Hamann K, Grabbe J, Welker P, Haas N, Algermissen B, Czarnetzki BM. Phenotypic evaluation of cultured human mast and basophilic cells and of Normal human skin mast cells. Arch Dermatol Res 1994;286:380-5. https://doi.org/10.1007/BF00371797
  44. Navi D, Saegusa J, Liu FT. Mast cells and immunological skin diseases. Clin Rev Allergy Immunol 2007;33:144-55. https://doi.org/10.1007/s12016-007-0029-4
  45. Hong CE, Lyu SY. Anti-inflammatory and anti-oxidative effects of Korean Red Ginseng extract in human keratinocytes. Immune Netw 2011;11:42-9. https://doi.org/10.4110/in.2011.11.1.42
  46. Qi XF, Kim DH, Yoon YS, Li JH, Song SB, Jin D, Huang XZ, Teng YC, Lee KJ. The adenylyl cyclase-cAMP system suppresses TARC/CCL17 and MDC/CCL22 production through p38 MAPK and NF-kappaB in HaCaT keratinocytes. Mol Immunol 2009;46:1925-34. https://doi.org/10.1016/j.molimm.2009.03.018
  47. Yano C, Saeki H, Komine M, Kagami S, Tsunemi Y, Ohtsuki M, Nakagawa H. Mechanism of macrophage-derived chemokine/CCL22 production by HaCaT keratinocytes. Ann Dermatol 2015;27:152-6. https://doi.org/10.5021/ad.2015.27.2.152

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