Skip to main content

Advertisement

SpringerLink
Log in

NB-UVB irradiation downregulates keratin-17 expression in keratinocytes by inhibiting the ERK1/2 and STAT3 signaling pathways

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

Keratin-17 (K17) is a cytoskeletal protein produced by keratinocytes (KCs), which is overexpressed in psoriasis and may play a pivotal role in its pathogenesis. Narrow-band ultraviolet B (NB-UVB) irradiation is used as a general treatment for psoriasis, although its impact on K17 expression has yet to be determined. In this study, we aimed to investigate the effect of NB-UVB irradiation on K17 expression and its signaling pathways. After exposure to NB-UVB irradiation, immortalized human keratinocytes (HaCaT cells) were analyzed by flow cytometry, CCK-8 assays and transmission electron microscopy to examine proliferation. Meanwhile, K17 expression in primary human epithelial keratinocytes was detected by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis and immunofluorescence. HaCaT cells pre-incubated with PD-98059 and piceatannol were subjected to western blot analysis to examine ERK1/2 and STAT3 phosphorylation. The ears of mice treated with imiquimod (IMQ) and irradiated by NB-UVB were taken to examine K17 expression by qRT-PCR, western blot analysis, and immunofluorescence. Our results showed that 400 mJ/cm2 of NB-UVB irradiation was the maximum tolerable dose for HaCaT cells and could cause inhibited HaCaT cell proliferation and moderate increase of the early apoptosis. Furthermore, NB-UVB irradiation could downregulate K17 expression by inhibiting the ERK1/2 and STAT3 signaling pathways. In experiments conducted in vivo, NB-UVB irradiation with doses of MED or higher could eliminate the IMQ-induced psoriasis-like dermatitis and inhibit K17 expression. These results indicated that NB-UVB irradiation may eliminate chronic psoriatic plaques by suppressing K17 expression via the ERK1/2 and STAT3 signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Arican O, Aral M, Sasmaz S, Ciragil P (2005) Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediat Inflamm 2005(5), 273–279

    Article  Google Scholar 

  2. Aufiero BM, Talwar H, Young C, Krishnan M, Hatfield JS, Lee HK, Wong HK, Hamzavi I, Murakawa GJ (2006) Narrow-band UVB induces apoptosis in human keratinocytes. J Photochem Photobiol B 82(2):132–139

    Article  CAS  PubMed  Google Scholar 

  3. Chang T, Sun L, Wang Y, Wang D, Li W, Li C, Gao T, Liu Y, Wang G (2011) Inhibition of keratin 17 expression with antisense and RNAi strategies: exploring novel therapy for psoriasis. Exp Dermatol, 20(7), 555–560

    Article  CAS  PubMed  Google Scholar 

  4. de Jong EM, van Vlijmen IM, van Erp PE, Ramaekers FC, Troyanovski SM, van de Kerkhof PC (1991) Keratin 17: a useful marker in anti-psoriatic therapies. Arch Dermatol Res 283(7):480–482

    Article  PubMed  Google Scholar 

  5. Del BS, Vioux C, Rossio-Pasquier P, Jomard A, Demarchez M, Asselineau D, Bernerd F (2004) Ultraviolet B induces hyperproliferation and modification of epidermal differentiation in normal human skin grafted on to nude mice. Br J Dermatol 150(4), 658–667

    Article  Google Scholar 

  6. Erkin G, Ugur Y, Gurer CK, Asan E, Korkusuz P, Sahin S, Kolemen F (2007) Effect of PUVA, narrow-band UVB and cyclosporin on inflammatory cells of the psoriatic plaque. J Cutan Pathol 34(3):213–219

    Article  PubMed  Google Scholar 

  7. Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M (2001) Keratins and the keratinocyte activation cycle. J Invest Dermatol, 116(5), 633–640

    Article  CAS  PubMed  Google Scholar 

  8. Fu M, Wang G (2012) Keratin 17 as a therapeutic target for the treatment of psoriasis. J Dermatol Sci 67(3):161–165

    Article  CAS  PubMed  Google Scholar 

  9. Gu X, Nylander E, Coates P, Nylander K (2015) Oxidation reduction is a key process for successful treatment of psoriasis by narrow-band UVB phototherapy. Acta Derm Venereol 95(2):140–146

    Article  PubMed  Google Scholar 

  10. Hachiya A, Sriwiriyanont P, Fujimura T, Ohuchi A, Kitahara T, Takema Y, Kitzmiller WJ, Visscher MO, Tsuboi R, Boissy RE (2009) Mechanistic effects of long-term ultraviolet B irradiation induce epidermal and dermal changes in human skin xenografts. Am J Pathol 174(2):401–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jiang M, Sun Z, Dang E, Li B, Fang H, Li J, Gao L, Zhang K, Wang G (2017) TGFbeta/SMAD/microRNA-486-3p signaling axis mediates keratin 17 expression and keratinocyte hyperproliferation in psoriasis. J Invest Dermatol 137(10):2177–2186

    Article  CAS  PubMed  Google Scholar 

  12. Jin L, Wang G (2014) Keratin 17: a critical player in the pathogenesis of psoriasis. Med Res Rev 34(2):438–454

    Article  CAS  PubMed  Google Scholar 

  13. Karantza V (2011) Keratins in health and cancer: more than mere epithelial cell markers. Oncogene 30(2):127–138

    Article  CAS  PubMed  Google Scholar 

  14. Kim S, Wong P, Coulombe PA (2006) A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 441(7091):362–365

    Article  CAS  PubMed  Google Scholar 

  15. Liao C, Xie G, Zhu L, Chen X, Li X, Lu H, Xu B, Ramot Y, Paus R, Yue Z (2016) p53 is a direct transcriptional repressor of keratin 17: lessons from a rat model of radiation dermatitis. J Invest Dermatol 136(3):680–689

    Article  CAS  PubMed  Google Scholar 

  16. Luo S, Peng Z, Zheng Y, Zhang L, Feng Y, Wang G (2007) Synergistic effects of acitretin and narrow-band UVB on inducing the expression of heparin-binding epidermal-growth-factor-like growth factor in normal human keratinocytes. Arch Dermatol Res, 299(8), 409–413

    Article  CAS  PubMed  Google Scholar 

  17. Luo S, Zheng Y, Peng Z, Jiang J, Gondokaryono S, Wang G, Ikeda S (2008) Effects of narrow-band ultraviolet B and tazarotene therapy on keratinocyte proliferation and TIG3 expression. J Dermatol 35(10):651–657

    Article  CAS  PubMed  Google Scholar 

  18. Nestle FO, Kaplan DH, Barker J (2009) Psoriasis. N Engl J Med 361(5):496–509

    Article  CAS  PubMed  Google Scholar 

  19. Ozawa M, Ferenczi K, Kikuchi T, Cardinale I, Austin LM, Coven TR, Burack LH, Krueger JG (1999) 312-nanometer ultraviolet B light (narrow-band UVB) induces apoptosis of T cells within psoriatic lesions. J Exp Med 189(4):711–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Paramio JM, Segrelles C, Lain S, Gomez-Casero E, Lane DP, Lane EB, Jorcano JL (2000) p53 is phosphorylated at the carboxyl terminus and promotes the differentiation of human HaCaT keratinocytes. Mol Carcinog 29(4), 251–262

    Article  CAS  PubMed  Google Scholar 

  21. Qin JZ, Chaturvedi V, Denning MF, Bacon P, Panella J, Choubey D, Nickoloff BJ (2002) Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes. Oncogene 21(19):2991–3002

    Article  CAS  PubMed  Google Scholar 

  22. Racz E, Kurek D, Kant M, Baerveldt EM, Florencia E, Mourits S, de Ridder D, Laman JD, van der Fits L, Prens EP (2011) GATA3 expression is decreased in psoriasis and during epidermal regeneration; induction by narrow-band UVB and IL-4. PLoS One 6(5):e19806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Racz E, Prens EP, Kurek D, Kant M, de Ridder D, Mourits S, Baerveldt EM, Ozgur Z, van IJcken WF, Laman JD, Staal FJ, van der Fits L (2011) Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathways. J Invest Dermatol 131(7):1547–1558

    Article  CAS  PubMed  Google Scholar 

  24. Reich A, Lehmann B, Meurer M, Muller DJ (2007) Structural alterations provoked by narrow-band ultraviolet B in immortalized keratinocytes: assessment by atomic force microscopy. Exp Dermatol 16(12):1007–1015

    Article  CAS  PubMed  Google Scholar 

  25. Reich A, Meurer M, Viehweg A, Muller DJ (2009) Narrow-band UVB-induced externalization of selected nuclear antigens in keratinocytes: implications for lupus erythematosus pathogenesis. Photochem Photobiol 85(1):1–7

    Article  CAS  PubMed  Google Scholar 

  26. Reich A, Schwudke D, Meurer M, Lehmann B, Shevchenko A (2010) Lipidome of narrow-band ultraviolet B irradiated keratinocytes shows apoptotic hallmarks. Exp Dermatol 19(8):e103-10

    PubMed  Google Scholar 

  27. Shen Z, Chen L, Liu YF, Gao TW, Wang G, Fan XL, Fan JY, Fan PS, Li CY, Liu B, Dang YP, Li CX (2006) Altered keratin 17 peptide ligands inhibit in vitro proliferation of keratinocytes and T cells isolated from patients with psoriasis. J Am Acad Dermatol 54(6):992–1002

    Article  PubMed  Google Scholar 

  28. Shi X, Jin L, Dang E, Chang T, Feng Z, Liu Y, Wang G (2011) IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. J Invest Dermatol 131(12):2401–2408

    Article  CAS  PubMed  Google Scholar 

  29. Sigmundsdottir H, Johnston A, Gudjonsson JE, Valdimarsson H (2005) Narrowband-UVB irradiation decreases the production of pro-inflammatory cytokines by stimulated T cells. Arch Dermatol Res 297(1):39–42

    Article  CAS  PubMed  Google Scholar 

  30. Sitailo LA, Tibudan SS, Denning MF (2002) Activation of caspase-9 is required for UV-induced apoptosis of human keratinocytes. J Biol Chem 277(22):19346–19352

    Article  CAS  PubMed  Google Scholar 

  31. Thewes M, Stadler R, Korge B, Mischke D (1991) Normal psoriatic epidermis expression of hyperproliferation-associated keratins. Arch Dermatol Res 283(7), 465–471

    Article  CAS  PubMed  Google Scholar 

  32. van Beelen AJ, Teunissen MB, Kapsenberg ML, de Jong EC (2007) Interleukin-17 in inflammatory skin disorders. Curr Opin Allergy Clin Immunol 7(5), 374–381

    Article  PubMed  Google Scholar 

  33. van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP, Lubberts E (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 182(9):5836–5845

    Article  PubMed  Google Scholar 

  34. Walters IB, Burack LH, Coven TR, Gilleaudeau P, Krueger JG (1999) Suberythemogenic narrow-band UVB is markedly more effective than conventional UVB in treatment of psoriasis vulgaris. J Am Acad Dermatol 40(6 Pt 1):893–900

    Article  CAS  PubMed  Google Scholar 

  35. Weatherhead SC, Farr PM, Jamieson D, Hallinan JS, Lloyd JJ, Wipat A, Reynolds NJ (2011) Keratinocyte apoptosis in epidermal remodeling and clearance of psoriasis induced by UV radiation. J Invest Dermatol 131(9):1916–1926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang L, Fan X, Cui T, Dang E, Wang G (2017) Nrf2 promotes keratinocyte proliferation in psoriasis through up-regulation of keratin 6, keratin 16, and keratin 17. J Investig Dermatol 137(10):2168–2176

    Article  CAS  PubMed  Google Scholar 

  37. Zhang W, Dang E, Shi X, Jin L, Feng Z, Hu L, Wu Y, Wang G (2012) The pro-inflammatory cytokine IL-22 up-regulates keratin 17 expression in keratinocytes via STAT3 and ERK1/2. PLoS One 7(7):e40797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81430073, 81402620, 81672692 and 81220108016).

Author information

Author notes

  1. Yuchen Zhuang, Changxu Han, Bing Li contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Yuchen Zhuang, Changxu Han, Bing Li, Liang Jin, Erle Dang, Hui Fang, Hongjiang Qiao & Gang Wang

Authors
  1. Yuchen Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Changxu Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erle Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongjiang Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gang Wang.

Ethics declarations

Conflict of interest

The authors have declared that no competing interest exists.

Ethical approval

The study protocol was approved by the Medical Research Ethics Committee at Xijing Hospital of the Fourth Military Medical University (Xi’an China). Written, informed consent was obtained from all participants prior to the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2137 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhuang, Y., Han, C., Li, B. et al. NB-UVB irradiation downregulates keratin-17 expression in keratinocytes by inhibiting the ERK1/2 and STAT3 signaling pathways. Arch Dermatol Res 310, 147–156 (2018). https://doi.org/10.1007/s00403-018-1812-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-018-1812-1

Keywords

Search

Navigation