DOI QR코드

DOI QR Code

Atopic Dermatitis-Related Inflammation in Macrophages and Keratinocytes: The Inhibitory Effects of Bee Venom

  • Kim, Deok-Hyun (Department of Acupuncture & Moxibustion Medicine, College of Korean Medicine, Gachon University) ;
  • Song, Ho-Sueb (Department of Acupuncture & Moxibustion Medicine, College of Korean Medicine, Gachon University)
  • Received : 2019.02.07
  • Accepted : 2019.04.19
  • Published : 2019.05.30

Abstract

Background: This study investigated the anti-inflammatory effects of bee venom (BV) through the inhibition of nuclear factor kappa beta ($NF-{\kappa}B$) expression in macrophages and keratinocytes. Methods: Cell viability assays were performed to investigate the cytotoxicity of BV in activated macrophages [lipopolysaccharide (LPS)] and keratinocytes [interferon-gamma/tumor necrosis factor-alpha ($IFN-{\gamma}/TNF-{\alpha}$)]. A luciferase assay was performed to investigate the cellular expression of $NF-{\kappa}B$ in relation to BV dose. The expression of $NF-{\kappa}B$ inhibitors ($p-I{\kappa}B{\alpha}$, $I{\kappa}B{\alpha}$, and p50 and p65) were determined by Western Blot analysis, and the electromobility shift assay. A nitrite quantification assay was performed to investigate the effect of BV, and $NF-{\kappa}B$ inhibitor on nitric oxide (NO) production in macrophages. In addition, Western Blot analysis was performed to investigate the effect of BV on the expression of mitogen-activated protein kinases (MAPK) in activated macrophages and keratinocytes. Results: BV was not cytotoxic to activated macrophages and keratinocytes. Transcriptional activity of $NF-{\kappa}B$, and p50, p65, and $p-I{\kappa}B{\alpha}$ expression was reduced by treatment with BV in activated macrophages and keratinocytes. Treatment with BV and an $NF-{\kappa}B$ inhibitor, reduced the production of NO by activated macrophages, and also reduced $NF-{\kappa}B$ transcriptional activity in activated keratinocytes (compared with either BV, or $NF-{\kappa}B$ inhibitor treatment). Furthermore, BV decreased p38, p-p38, JNK, and p-JNK expression in LPS-activated macrophages and $IFN-{\gamma}/TNF-{\alpha}$-activated keratinocytes. Conclusion: BV blocked the signaling pathway of $NF-{\kappa}B$, which plays an important role in the inflammatory response in macrophages and keratinocytes. These findings provided the possibility of BV in the treatment of atopic dermatitis.

Keywords

References

  1. Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 2011;242:233-246. https://doi.org/10.1111/j.1600-065X.2011.01027.x
  2. Wakao S, Kuroda Y, Ogura F, Shigemoto T, Dezawa M. Regenerative effects of mesenchymal stem cells: contribution of muse cells, a novel pluripotent stem cell type that resides in mesenchymal cells. Cells 2012;1:1045-1060. https://doi.org/10.3390/cells1041045
  3. Mirza R, DiPietro LA, Koh TJ. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol 2009;175:2454-2462. https://doi.org/10.2353/ajpath.2009.090248
  4. Kasraie S, Werfel T. Role of macrophages in the pathogenesis of atopic dermatitis. Mediators Inflamm 2013;2013:942375.
  5. Raingeaud J, Pierre J. Interleukin-4 downregulates $TNF{\alpha}$-induced IL-8 production in keratinocytes. FEBS Letter 2005;579:3953-3959. https://doi.org/10.1016/j.febslet.2005.06.019
  6. Fujihara M, Muroi M, Tanamoto K, Suzuki T, Azuma H, Ikeda H. Molecular mechanisms of macrophage activation and deactivation by lipopolysaccharide: roles of the receptor complex. Pharmacol Ther 2003;100:171-194. https://doi.org/10.1016/j.pharmthera.2003.08.003
  7. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signaling pathways in cancer. Oncogene 2007;26:3279-3290. https://doi.org/10.1038/sj.onc.1210421
  8. Schaeffer HJ, Weber MJ. Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 1999;19:2435-2444. https://doi.org/10.1128/MCB.19.4.2435
  9. Longpre F, Garneau P, Christen Y, Ramassamy C. Protection by EGb 761 against beta-amyloid-induced neurotoxicity: involvement of NF-kappaB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation. Free Radic Biol Med 2006;41:1781-1794. https://doi.org/10.1016/j.freeradbiomed.2006.08.015
  10. Reber L, Vermeulen L, Haegeman G, Frossard N. Ser276 phosphorylation of NF-${\kappa}B$ p65 by MSK1 controls SCF expression in inflammation. PLoS One 2009;4:e4393. https://doi.org/10.1371/journal.pone.0004393
  11. Hiscott J, Kwon H, Genin P. Hostile takeovers: Viral appropriation of the NF-kappaB pathway. J Clin Invest 2001;107:143-151. https://doi.org/10.1172/JCI11918
  12. Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 2006;72:1493-1505. https://doi.org/10.1016/j.bcp.2006.04.011
  13. Kim KH, Lee WR, An HJ, Kim JY, Chung H, Han SM et al. Bee venom ameliorates compound 48/80-induced atopic dermatitis-related symptoms. Int J Clin Exp Pathol 2013;6:2896-2903.
  14. Park HJ, Lee SH, Son DJ, Oh KW, Kim KH, Song HS et al. Antiarthritic effect of bee venom: inhibition of inflammation mediator generation by suppression of NF-kappaB through interaction with the p50 subunit. Arthritis Rheum 2004;50:3504-3515. https://doi.org/10.1002/art.20626
  15. Boguniewicz M, Leung DY. Recent insights into atopic dermatitis and implications for management of infectious complications. J Allergy Clin Immunol 2010;125:4-13. https://doi.org/10.1016/j.jaci.2009.11.027
  16. Niebuhr M, Werfel T. Innate immunity, allergy and atopic dermatitis. Curr Opin Allergy Clin Immunol 2010;10:463-468. https://doi.org/10.1097/ACI.0b013e32833e3163
  17. Novak N, Simon D. Atopic dermatitis-from new pathophysiologic insights to individualized therapy. Allergy 2010;66:830-839. https://doi.org/10.1111/j.1398-9995.2011.02571.x
  18. Guttman-Yassky E, Nograles KE, Krueger, JG. Contrasting pathogenesis of atopic dermatitis and psoriasis-Part I: clinical and pathologic concepts. J Allergy Clin Immunol 2011;127:1110-1118. https://doi.org/10.1016/j.jaci.2011.01.053
  19. Guttman-Yassky E, Nograles KE, Krueger, JG. Contrasting pathogenesis of atopic dermatitis and psoriasis-part II: immune cell subsets and therapeutic concepts. J Allergy Clin Immunol 2011;127:1420-1432. https://doi.org/10.1016/j.jaci.2011.01.054
  20. Novak N, Bieber T, Leung DY. Immune mechanisms leading to atopic dermatitis. J Allergy Clin Immunol 2003;112:S128-S139. https://doi.org/10.1016/j.jaci.2003.09.032
  21. Kiekens RCM, Thepen T, Oosting AJ, Bihari IC, Van de Winkel JGJ, Bruijnzeel-Koomen CAFM et al. Heterogeneity within tissue-specific macrophage and dendritic cell populations during cutaneous inflammation in atopic dermatitis. Br J Dermatol 2001;145:957-965. https://doi.org/10.1046/j.1365-2133.2001.04508.x
  22. McCoy CE, O'Neill LA. The role of toll-like receptors in macrophages. Front Biosci 2008;13:62-70. https://doi.org/10.2741/2660
  23. Kee JY, Jeon YD, Kim DS, Han YH, Park J, Youn DH et al. Korean red ginseng improves atopic dermatitis-like skin lesions by suppressing expression of proinflammatory cytokines and chemokines in vivo and in vitro. J Ginseng Res 2017;41:134-143. https://doi.org/10.1016/j.jgr.2016.02.003
  24. Lim HS, Kim YJ, Seo CS, Yoo SR, Jin SE, Shin HK et al. Chungsimyeonjaeum inhibits inflammatory responses in RAW 264.7 macrophages and HaCaT keratinocytes. BMC Complement Altern Med 2015;15:371. https://doi.org/10.1186/s12906-015-0902-2
  25. Seo WY, Youn GS, Choi SY, Park J. Butein, a tetrahydroxychalcone, suppresses pro-inflammatory responses in HaCaT keratinocytes. BMB Rep 2015;48:495-500. https://doi.org/10.5483/BMBRep.2015.48.9.259
  26. Yang JH, Hwang YH, Gu MJ, Cho WK, Ma JY. Ethanol extracts of Sanguisorba officinalis L. suppress TNF-$\alpha$/IFN-$\gamma$-induced pro-inflammatory chemokine production in HaCaT cells. Phytomedicine 2015;22:1262-1268. https://doi.org/10.1016/j.phymed.2015.09.006
  27. Lee KG, Cho HJ, Bae YS, Park KK, Choe JY, Chung IK et al. Bee venom suppresses LPS-mediated NO/iNOS induction through inhibition of PKCalpha expression. J Ethnopharmacol 2009;123:15-21. https://doi.org/10.1016/j.jep.2009.02.044
  28. Kim SJ, Park JH, Kim KH, Lee WR, Chang YC, Park KK et al. Bee venom inhibits hepatic fibrosis through suppression of pro-fibrogenic cytokine expression. Am J Chin Med 2010;38:921-935. https://doi.org/10.1142/S0192415X10008354
  29. Yoon SY, Kwon YB, Kim HW, Roh DH, Seo HS, Han HJ et al. Peripheral bee venom's anti-inflammatory effect involves activation of the coeruleospinal pathway and sympathetic preganglionic neurons. Neurosci Res 2007;59:51-59. https://doi.org/10.1016/j.neures.2007.05.008
  30. Sur B, Lee B, Yeom M, Hong JH, Kwon S, Kim ST et al. Bee venom acupuncture alleviates trimellitic anhydride-induced atopic dermatitis-like skin lesions in mice. BMC Complement Altern Med 2016;16:38.
  31. An HJ, Kim JY, Kim WH, Gwon MG, Gu HM, Jeon MJ et al. Therapeutic effects of bee venom and its major component, melittin, on atopic dermatitis in vivo and in vitro. Br J Pharmacol 2018;175:4310-4324. https://doi.org/10.1111/bph.14487
  32. Jung KH, Baek H, Kang M, Kim N, Lee SY, Bae H. Bee Venom Phospholipase A2 Ameliorates House Dust Mite Extract Induced Atopic Dermatitis Like Skin Lesions in Mice. Toxins (Basel) 2017;9:68. https://doi.org/10.3390/toxins9020068
  33. Gu H, Kim WH, An HJ, Kim JY, Gwon MG, Han SM et al. Therapeutic effects of bee venom on experimental atopic dermatitis. Mol Med Rep 2018;18:3711-3718. https://doi.org/10.3892/mmr.2018.9398
  34. Jeon YJ, Kim YK, Lee M, Park SM, Han SB, Kim HM. Radicicol suppresses expression of inducible nitric-oxide synthase by blocking p38 kinase and nuclear factor-${\kappa}B$/Rel in lipopolysaccharide-stimulated macrophages. J Pharmacol Exp Ther 2000;294:548-554.
  35. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-${\kappa}B$ activation. Mutat Res 2001;480-481:243-268. https://doi.org/10.1016/S0027-5107(01)00183-X
  36. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J 2001;357:593-615. https://doi.org/10.1042/bj3570593
  37. Bogdan C. Nitric oxide and the immune response. Nat Immunol 2001;2:907-916. https://doi.org/10.1038/ni1001-907
  38. Cario E, Rosenberg IM, Brandwein SL, Beck PL, Reinecker HC, Podolsky DK. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J Immunol 2000;164:966-972. https://doi.org/10.4049/jimmunol.164.2.966
  39. Zhang FX, Kirschning CJ, Mancinelli R, Xu XP, Jin Y, Faure E et al. Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem 1999;274:7611-7614. https://doi.org/10.1074/jbc.274.12.7611
  40. Kuprash DV, Udalova IA, Turetskaya RL, Kwiatkowski D, Rice NR, Nedospasov SA. Similarities and differences between human and murine TNF promoters in their response to lipopolysaccharide. J Immunol 1999;162:4045-4052.
  41. Rudders S, Gaspar J, Madore R, Voland C, Grall F, Patel A et al. ESE-1 is a novel transcriptional mediator of inflammation that interacts with NF-${\kappa}B$ to regulate the inducible nitric-oxide synthase gene. J Biol Chem 2001;276:3302-3309. https://doi.org/10.1074/jbc.M006507200
  42. Lee SY, Son DJ, Lee YK, Lee JW, Lee HJ, Yun YW et al. Inhibitory effect of sesaminol glucosides on lipopolysaccharide-induced NF-kappaB activation and target gene expression in cultured rat astrocytes. Neurosci Res 2006;56:204-212. https://doi.org/10.1016/j.neures.2006.06.005
  43. Tsao LT, Tsai PS, Lin RH, Huang LJ, Kuo SC, Wang JP. Inhibition of lipopolysaccharide-induced expression of inducible nitric oxide synthase by phenolic (3E)-4-(2-hydroxyphenyl)but-3-en-2-one in RAW 264.7 macrophages. Biochem Pharmacol 2005;70:618-626. https://doi.org/10.1016/j.bcp.2005.05.032
  44. Zhao Q, Lee FS. Mitogen-activated protein kinase/ERK kinase kinases 2 and 3 activate nuclear factor-${\kappa}B$ through $I{\kappa}B$ kinase-$\alpha$ and $I{\kappa}B$ kinase-${\beta}$. J Biol Chem 1999;274:8355-8358. https://doi.org/10.1074/jbc.274.13.8355

Cited by

  1. Bee venom ameliorates cardiac dysfunction in diabetic hyperlipidemic rats vol.246, pp.24, 2021, https://doi.org/10.1177/15353702211045924