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Galvanic zinc–copper microparticles produce electrical stimulation that reduces the inflammatory and immune responses in skin

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Abstract

The human body has its own innate electrical system that regulates the body’s functions via communications among organs through the well-known neural system. While the effect of low-level electrical stimulation on wound repair has been reported, few studies have examined the effect of electric potential on non-wounded, intact skin. A galvanic couple comprised of elemental zinc and copper was used to determine the effects of low-level electrical stimulation on intact skin physiology using a Dermacorder device. Zn–Cu induced the electrical potential recorded on intact skin, enhanced H2O2 production and activated p38 MAPK and Hsp27 in primary keratinocytes. Treatment with Zn–Cu was also found to reduce pro-inflammatory cytokines, such as IL-1α, IL-2, NO and TNF-α in multiple cell types after stimulation with PHA or Propionibacterium acnes bacteria. The Zn–Cu complex led to a dose-dependent inhibition of TNF-α-induced NF-κB levels in keratinocytes as measured by a dual-luciferase promoter assay, and prevented p65 translocation to the nucleus observed via immunofluorescence. Suppression of NF-κB activity via crosstalk with p38 MAPK might be one of the potential pathways by which Zn–Cu exerted its inflammatory effects. Topical application of Zn–Cu successfully mitigated TPA-induced dermatitis and oxazolone-induced hypersensitivity in mice models of ear edema. Anti-inflammatory activity induced by the Zn–Cu galvanic couple appears to be mediated, at least in part, by production of low level of hydrogen peroxide since this activity is reversed by the addition of Catalase enzyme. Collectively, these results show that a galvanic couple containing Zn–Cu strongly reduces the inflammatory and immune responses in intact skin, providing evidence for the role of electric stimulation in non-wounded skin.

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Abbreviations

PHA:

Phytohemagglutinin

PBMC:

Peripheral blood mononuclear cells

TPA:

Tetradecanoyl phorbol acetate

TNF-α:

Tumor necrosis factor-α

IL-2:

Interleukin-2

IL-6:

Interleukin-6

IL-10:

Interleukin-10

IL-12:

Interleukin-12

GM-CSF:

Granulocyte macrophage colony-stimulating factor

COX-2:

Cyclo-oxygenase-2

PGE2 :

Prostaglandin E2

P. acnes :

Propionibacterium acnes

NO:

Nitric oxide

RT:

Room temperature

H2O2 :

Hydrogen peroxide

PI(3)K:

Phosphatidylinositol-3-OH kinase

PTEN:

Phosphatase and tensin homolog

References

  1. Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, Ben-Neriah Y (1995) Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin–proteasome pathway. Proc Natl Acad Sci USA 92:10599–10603

    Article  PubMed  CAS  Google Scholar 

  2. Anderson MT, Staal FJ, Gitler C, Herzenberg LA, Herzenberg LA (1994) Separation of oxidant-initiated and redox-regulated steps in the NF-kappa B signal transduction pathway. Proc Natl Acad Sci USA 91:11527–11531

    Article  PubMed  CAS  Google Scholar 

  3. Beg AA, Finco TS, Nantermet PV, Baldwin AS Jr (1993) Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation. Mol Cell Biol 13:3301–3310

    PubMed  CAS  Google Scholar 

  4. Blanc A, Pandey NR, Srivastava AK (2003) Synchronous activation of ERK 1/2, p38mapk and PKB/Akt signaling by H2O2 in vascular smooth muscle cells: potential involvement in vascular disease (review). Int J Mol Med 11:229–234

    PubMed  CAS  Google Scholar 

  5. Bowie AG, Moynagh PN, O’Neill LA (1997) Lipid peroxidation is involved in the activation of NF-kappa B by tumor necrosis factor but not interleukin-1 in the human endothelial cell line ECV304. Lack of involvement of H2O2 in NF-kappa B activation by either cytokine in both primary and transformed endothelial cells. J Biol Chem 272:25941–25950

    Article  PubMed  CAS  Google Scholar 

  6. Brighton CT, Wang W, Seldes R, Zhang G, Pollack SR (2001) Signal transduction in electrically stimulated bone cells. J Bone Joint Surg Am 83-A:1514–1523

    PubMed  CAS  Google Scholar 

  7. Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267:1485–1488

    Article  PubMed  CAS  Google Scholar 

  8. Chernyavsky AI, Arredondo J, Karlsson E, Wessler I, Grando SA (2005) The Ras/Raf-1/MEK1/ERK signaling pathway coupled to integrin expression mediates cholinergic regulation of keratinocyte directional migration. J Biol Chem 280:39220–39228

    Article  PubMed  CAS  Google Scholar 

  9. Driban JB, Swanik CB, Huxel KC, Balsubramanian E (2007) Transient electric changes immediately after surgical trauma. J Athl Train 42:524–529

    PubMed  Google Scholar 

  10. Fenton MJ (1992) Review: transcriptional and post-transcriptional regulation of interleukin 1 gene expression. Int J Immunopharmacol 14:401–411

    Article  PubMed  CAS  Google Scholar 

  11. Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L (1997) Redox regulation of NF-kappa B activation. Free Radic Biol Med 22:1115–1126

    Article  PubMed  CAS  Google Scholar 

  12. Grandjean-Laquerriere A, Le Naour R, Gangloff SC, Guenounou M (2005) Contribution of protein kinase A and protein kinase C pathways in ultraviolet B-induced IL-8 expression by human keratinocytes. Cytokine 29:197–207

    Article  PubMed  CAS  Google Scholar 

  13. Griendling KK, Ushio-Fukai M (2000) Reactive oxygen species as mediators of angiotensin II signaling. Regul Pept 91:21–27

    Article  PubMed  CAS  Google Scholar 

  14. Guerin-Marchand C, Senechal H, Pelletier C, Fohrer H, Olivier R, David B, Berthon B, Blank U (2001) H2O2 impairs inflammatory mediator release from immunologically stimulated RBL-2H3 cells through a redox-sensitive, calcium-dependent mechanism. Inflamm Res 50:341–349

    Article  PubMed  CAS  Google Scholar 

  15. Guo A, Song B, Reid B, Gu Y, Forrester JV, Jahoda CA, Zhao M (2010) Effects of physiological electric fields on migration of human dermal fibroblasts. J Invest Dermatol 130:2320–2327

    Google Scholar 

  16. Hayakawa M, Miyashita H, Sakamoto I, Kitagawa M, Tanaka H, Yasuda H, Karin M, Kikugawa K (2003) Evidence that reactive oxygen species do not mediate NF-kappaB activation. EMBO J 22:3356–3366

    Article  PubMed  CAS  Google Scholar 

  17. Hodges SD, Eck JC, Humphreys SC (2003) Use of electrical bone stimulation in spinal fusion. J Am Acad Orthop Surg 11:81–88

    PubMed  Google Scholar 

  18. Huttenlocher A, Horwitz AR (2007) Wound healing with electric potential. N Engl J Med 356:303–304

    Article  PubMed  CAS  Google Scholar 

  19. Ikeda M, Hirose Y, Miyoshi K, Kodama H (2002) Nuclear factor kappaB (NF-kappaB) activation by hydrogen peroxide in human epidermal keratinocytes and the restorative effect of interleukin-10. J Dermatol Sci 28:159–170

    Article  PubMed  CAS  Google Scholar 

  20. Jennings J, Chen D, Feldman D (2008) Transcriptional response of dermal fibroblasts in direct current electric fields. Bioelectromagnetics 29:394–405

    Article  PubMed  CAS  Google Scholar 

  21. Jennings JA, Chen D, Feldman DS (2010) Upregulation of chemokine (C-C motif) ligand 20 in adult epidermal keratinocytes in direct current electric fields. Arch Dermatol Res 302:211-220

    Google Scholar 

  22. Keum YS, Yu S, Chang PP, Yuan X, Kim JH, Xu C, Han J, Agarwal A, Kong AN (2006) Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells. Cancer Res 66:8804–8813

    Article  PubMed  CAS  Google Scholar 

  23. Larmour IA, Bell SE, Saunders GC (2007) Remarkably simple fabrication of superhydrophobic surfaces using electroless galvanic deposition. Angew Chem Int Ed Engl 46:1710–1712

    Article  PubMed  CAS  Google Scholar 

  24. Lee BY, Wendell K, Al-Waili N, Butler G (2007) Ultra-low microcurrent therapy: a novel approach for treatment of chronic resistant wounds. Adv Ther 24:1202–1209

    Article  PubMed  CAS  Google Scholar 

  25. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN (2001) Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol 2:612–619

    Article  PubMed  CAS  Google Scholar 

  26. Liebel F, Lyte P, Garay M, Babad J, Southall MD (2006) Anti-inflammatory and anti-itch activity of sertaconazole nitrate. Arch Dermatol Res 298:191–199

    Article  PubMed  CAS  Google Scholar 

  27. Ligier V, Wery M et al (1999) Formation of the main atomospheric zinc end products: NaZn4(OH)6·6H2O, Zn4SO4(OH)6·nH2O and Zn4Cl2(OH)4SO4.5H2O in [Cl][SO4 2−][HCO3 ][H2O2] Electrolytes. Corros Sci 41:1139–1164

    Article  CAS  Google Scholar 

  28. Lloret S, Moreno JJ (1995) Effects of an anti-inflammatory peptide (antiflammin 2) on cell influx, eicosanoid biosynthesis and oedema formation by arachidonic acid and tetradecanoyl phorbol dermal application. Biochem Pharmacol 50:347–353

    Article  PubMed  CAS  Google Scholar 

  29. Maniatis T (1999) A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev 13:505–510

    Article  PubMed  CAS  Google Scholar 

  30. Marx JL (1981) Electric currents may guide development. Science 211:1147–1149

    Article  PubMed  CAS  Google Scholar 

  31. McCaig CD, Zhao M (1997) Physiological electrical fields modify cell behaviour. Bioessays 19:819–826

    Article  PubMed  CAS  Google Scholar 

  32. Mendonca FA, Passarini Junior JR, Esquisatto MA, Mendonca JS, Franchini CC, Santos GM (2009) Effects of the application of Aloe vera (L.) and microcurrent on the healing of wounds surgically induced in Wistar rats. Acta Cir Bras 24:150–155

    Article  PubMed  Google Scholar 

  33. Mitra S, Abraham E (2006) Participation of superoxide in neutrophil activation and cytokine production. Biochim Biophys Acta 1762:732–741

    PubMed  CAS  Google Scholar 

  34. Moncada S, Ferreira SH, Vane JR (1973) Prostaglandins, aspirin-like drugs and the oedema of inflammation. Nature 246:217–219

    Article  PubMed  CAS  Google Scholar 

  35. Mori N, Prager D (1996) Transactivation of the interleukin-1alpha promoter by human T-cell leukemia virus type I and type II Tax proteins. Blood 87:3410–3417

    PubMed  CAS  Google Scholar 

  36. Morris KA, McGee MF, Jasper JJ, Bogie KM (2009) Evaluation of electrical stimulation for ischemic wound therapy: a feasibility study using the lapine wound model. Arch Dermatol Res 301:323–327

    Article  PubMed  Google Scholar 

  37. Ojingwa JC, Isseroff RR (2003) Electrical stimulation of wound healing. J Invest Dermatol 121:1–12

    Article  PubMed  CAS  Google Scholar 

  38. Otkjaer K, Holtmann H, Kragstrup TW, Paludan SR, Johansen C, Gaestel M, Kragballe K, Iversen L (2010) The p38 MAPK regulates IL-24 expression by stabilization of the 3′ UTR of IL-24 mRNA. PLoS One 5:e8671

    Google Scholar 

  39. Pullar CE, Isseroff RR (2005) Cyclic AMP mediates keratinocyte directional migration in an electric field. J Cell Sci 118:2023–2034

    Article  PubMed  CAS  Google Scholar 

  40. Rai R, Srinivas CR (2005) Iontophoresis in dermatology. Indian J Dermatol Venereol Leprol 71:236–241

    Article  PubMed  Google Scholar 

  41. Rao TS, Currie JL, Shaffer AF, Isakson PC (1993) Comparative evaluation of arachidonic acid (AA)- and tetradecanoylphorbol acetate (TPA)-induced dermal inflammation. Inflammation 17:723–741

    Article  PubMed  CAS  Google Scholar 

  42. Reid B, Nuccitelli R, Zhao M (2007) Non-invasive measurement of bioelectric currents with a vibrating probe. Nat Protoc 2:661–669

    Article  PubMed  CAS  Google Scholar 

  43. Sauer H, Rahimi G, Hescheler J, Wartenberg M (1999) Effects of electrical fields on cardiomyocyte differentiation of embryonic stem cells. J Cell Biochem 75:710–723

    Article  PubMed  CAS  Google Scholar 

  44. Schieven GL (2005) The biology of p38 kinase: a central role in inflammation. Curr Top Med Chem 5:921–928

    Article  PubMed  CAS  Google Scholar 

  45. Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. EMBO J 10:2247–2258

    PubMed  CAS  Google Scholar 

  46. Slack JM (2007) The spark of life: electricity and regeneration. Sci STKE 405:pe54

    Google Scholar 

  47. Subramony JA, Sharma A, Phipps JB (2006) Microprocessor controlled transdermal drug delivery. Int J Pharm 317:1–6

    Article  PubMed  CAS  Google Scholar 

  48. Sur R, Babad JM, Garay M, Liebel FT, Southall MD (2008) Anti-inflammatory activity of sertaconazole nitrate is mediated via activation of a p38-COX-2-PGE2 pathway. J Invest Dermatol 128:336–344

    Article  PubMed  CAS  Google Scholar 

  49. Zhang L, Tinkle SS (2000) Chemical activation of innate and specific immunity in contact dermatitis. J Invest Dermatol 115:168–176

    Article  PubMed  CAS  Google Scholar 

  50. Zmijewski JW, Zhao X, Xu Z, Abraham E (2007) Exposure to hydrogen peroxide diminishes NF-kappaB activation, IkappaB-alpha degradation, and proteasome activity in neutrophils. Am J Physiol Cell Physiol 293:C255–C266

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Runa Sur and Jeanette Chantalat for technical assistance.

Conflict of interest

All authors are current employees of Johnson & Johnson. Parts of this work have been presented in a poster format at the Society for Investigative Dermatology Annual Meeting, Atlanta (GA), 2010, and American Academy of Dermatology Annual Meeting, Miami, (FL) 2010.

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Correspondence to Michael D. Southall.

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Kaur, S., Lyte, P., Garay, M. et al. Galvanic zinc–copper microparticles produce electrical stimulation that reduces the inflammatory and immune responses in skin. Arch Dermatol Res 303, 551–562 (2011). https://doi.org/10.1007/s00403-011-1145-9

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  • DOI: https://doi.org/10.1007/s00403-011-1145-9

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