Journal of Applied Biological Chemistry

The Korean Society for Applied Biological Chemistry (한국응용생명화학회)
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Brazilin downregulates CCL20 expression via regulation of STAT3 phosphorylation in TNF-α/IL-17A/IFN-γ-induced HaCaT cells

TNF-α/IL-17A/IFN-γ 유도된 HaCaT 세포에서 브라질린의 STAT3 인산화 억제를 통한 CCL20 저해 효과

  • Received : 2021.05.13
  • Accepted : 2021.06.10
  • Published : 2021.06.30
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Abstract

Psoriasis is a chronic intractable skin disease caused by various inflammatory cytokines such as IL-6, CXCL8, TNF-α, and IFN-γ, as well as IL-17A secreted from Th17 cells and is characterized by hyperkeratosis and chronic inflammation of the epidermis. Brazilin, an active ingredient of Caesalpinia sappan L., is known to exert antioxidant and anti-inflammatory activity, and function in skin barrier improvement. In particular, it was shown as a potential material for treating psoriasis in a tumor necrosis factor (TNF)-α-stimulated HaCaT keratinocyte model. However, the direct regulation of the C-C motif chemokine ligand (CCL) 20, a psoriasis-inducing factor, by brazilin has not been reported. Therefore, in this study, we investigated the suppression of CCL20 and the regulatory mechanism by brazilin using a psoriasis-like model. First, brazilin downregulated CCL20 and CXCL8 in IL-17A-stimulated HaCaT cells in a concentration-dependent manner by inhibiting signal transducer and transcription (STAT)3 phosphorylation. In addition, brazilin significantly inhibited the expression of psoriasis-related genes CXCL8, CCL20, IL-1, IL-6, and TNF-α in TNF-α/IL-17A/IFN-γ-stimulated HaCaT cells. Moreover, brazilin also had a positive effect on improving the skin barrier in TNF-α/IL-17A/IFN-γ-stimulated HaCaT cells. The above results indicated that brazilin ultimately downregulated CCL20 expression by inhibiting STAT3 phosphorylation, and also suppressed the expression of psoriasis-induced cytokines. If the efficacy of brazilin in improving psoriasis is verified through animal models and clinical trials in the future, it may represent a potentially therapeutic substance for psoriasis patients.

건선(Psoriasis)은 IL-6, CXCL8, TNF-α 및 IFN-γ뿐만 아니라 Th17 세포에서 분비되는 IL-17A 등 다양한 염증성 사이토카인에 의해 표피의 과증식(hyperkeratosis) 및 만성적 염증(inflammation)이 유발되는 난치성 피부 질환이다. 소목(Caesalpinia sappan L.)의 유효성분으로 알려진 브라질린(brazilin)은 항산화, 항염증 및 피부 장벽 개선 등의 효능이 알려졌다. 특히, tumor necrosis factor (TNF)-α 자극 HaCaT 각질형성세포 모델에서 브라질린의 건선 치료 소재 가능성을 보여주었다. 그러나, 직접적인 건선 유발 인자인 C-C motif chemokine ligand (CCL) 20의 조절은 전혀 보고되지 않았다. 따라서, 본 연구에서는 건선 유사 모델을 활용해 CCL20 발현 조절 여부 및 그 기작에 대해 규명하고자 하였다. IL-17A로 자극된 HaCaT 세포에서 브라질린은 CCL20, CXCL8 발현 및 signal transducer and transcription (STAT)3 인산화를 유의하게 억제하였다. 또한, 브라질린은 TNF-α/IL-17A/IFN-γ 3종 사이토카인으로 처리된 조건에서도 STAT3 인산화를 억제하며 염증성 분자(CXCL8, CCL20, IL-1, IL-6, 및 TNF-α)의 발현을 하향 조절하였다. 마지막으로 브라질린은 TNF-α/IL-17A/IFN-γ로 자극된 건선 유사 환경에서 피부 장벽 개선에도 유의적인 영향을 미쳤다. 위 결과들을 통해 우리는 궁극적으로 브라질린이 STAT3 인산화 억제를 통해 CCL20 발현을 하향 조절하며, 건선 유발 사이토카인들의 발현 또한 억제함을 알 수 있었다. 향후, 건선 동물모델 및 임상시험을 통해 브라질린의 건선 개선에 대한 효능이 검증된다면, 건선 환자에게 잠재적인 치료 물질로 사용될 수 있을 것으로 기대된다.

Keywords

References

  1. Sun S, Zhang X, Xu M, Zhang F, Tian. F, Cui. J, Xia Y, Liang C, Zhou Shujie, Wei H, Zhao Hui, Wu G, Xu Bohan, Liu X, Yang G, Wang Q, Zhang L, Gong Y, Shao C, Zou Y (2019) Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes. Cell Death Dis 10: 274 https://doi.org/10.1038/s41419-019-1510-8
  2. Roberson EDO, Bowcock AM (2010) Psoriasis genetics: breaking the barrier. Trends Genet 26: 415-423. doi: 10.1016/j.tig.2010.06.006
  3. Langley RGB, Krueger GG, Griffiths CEM (2005) Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 64: ii18-ii23. doi: 10.1136/ard.2004.033217
  4. Kimball AB, Gladman D, Gelfand JM, Gordon K, Horn EJ, Korman NJ, Korver G, Krueger GG, Strober BE, Lebwohl MG (2008) National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad Dermatol 58: 1031-1042. doi: 10.1016/j.jaad.2008.01.006
  5. Vlachos C, Gaitanis G, Katsanos KH, Christodoulou DK, Tsianos E, Bassukas ID (2016) Psoriasis and inflammatory bowel disease: links and risks. Psoriasis (Auckl) 6: 73-92. doi: 10.2147/PTT.S85194
  6. Oliveira MFSPD, Rocha BO, Duarte GV (2015) Psoriasis: classical and emerging comorbidities. An Bras Dermatol 90: 9-20. doi: 10.1590/abd1806-4841
  7. Rendon A, Schakel K (2019) Psoriasis pathogenesis and treatment. Int J Mol Sci 20: 1475. doi: 10.3390/ijms20061475
  8. Christophers E (2001) Psoriasis-epidemiology and clinical spectrum. Clin Exp Dermatol 26: 314-320. doi: 10.1046/j.1365-2230.2001.00832.x
  9. Alzahrani KS, Nadeem A, Ahmad SF, Al-Harbi NO, Ibrahim KE, El-Sherbeeny AM, Alhoshani AR, Alshammari MA, Alotaibi MR, Al-Harbi MM (2019) Inhibition of spleen tyrosine kinase attenuates psoriasis-like inflammation in mice through blockade of dendritic cell-Th17 inflammation axis. Biomed Pharmacother 111: 347-358. doi: 10.1016/j.biopha.2018.12.060
  10. Lowes MA, Suarez-Farinas M, Krueger JG (2014) Immunology of psoriasis. Ann Rev Immunol 32: 227-255. doi: 10.1146/annurevimmunol-032713-120225
  11. Pirowska M, Obtulowicz A, Lipko-Godlewska S, Gozdzialska A, Podolec K, Wojas-Pelc A (2018) The level of proinflammatory cytokines: interleukins 12, 23, 17 and tumor necrosis factor α in patients with metabolic syndrome accompanying severe psoriasis and psoriatic arthritis. Postepy Dermatol Alergol 35: 360-366. doi: 10.5114/ada.2018.77665
  12. Johansen C, Usher PA, Kjellerup RB, Lundsgaard D, Iversen L, Kragballe K (2009) Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol 160: 319-324. doi: 10.1111/j.1365-2133.2008.08902.x
  13. McGeachy MJ, Cua DJ, Gaffen SL (2019) The IL-17 family of cytokines in health and disease. Immunity 50: 892-906. doi: 10.1016/j.immuni.2019.03.021
  14. Brembilla NC, Senra L, Boehncke WH (2018) The IL-17 family of cytokines in psoriasis: IL-17A and beyond. Front Immunol 9: 1682. doi: 10.3389/fimmu.2018.01682
  15. Furue K, Ito T, Tsuji G, Nakahara T, Furue M (2020) The CCL20 and CCR6 axis in psoriasis. Scandi J Immunol 91: e12846. doi: 10.1111/sji.12846
  16. Bartlett HS, Million RP (2014) Targeting the IL-17-T H 17 pathway. Nat Rev Drug Discov 14: 11-12 https://doi.org/10.1038/nrd4518
  17. Wu L, Chen X, Zhao J, Martin B, Zepp JA, Ko JS, Gu C, Cai G, Ouyang W, Sen G, Stark GR, Su B, Vines CM, Toumier C, Hamilton TA, Vidimos A, Gastman B, Liu C, Li X (2015) A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis. J Exp Med 212: 1571-1587. doi: 10.1084/jem.20150204
  18. Chiricozzi A, Guttman-Yassky E, Suarez-Farinas M, Nograles KE, Tian S, Cardinale I, Chimenti S, Krueger JG (2011) Integrative responses to IL-17 and TNF-α in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 131: 677-687. doi: 10.1038/jid.2010.340
  19. Blauvelt A, Chiricozzi A (2018) The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clini Rev Allergy Immunol 55: 379-390 https://doi.org/10.1007/s12016-018-8702-3
  20. Calautti E, Avalle L, Poli V (2018) Psoriasis: a STAT3-centric view. Int J Mol Sci 19: 171. doi: 10.3390/ijms19010171
  21. Li Q, Laumonnier Y, Syrovets T, Simmet T (2013) Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin-stimulated macrophages. Acta Biochim Biophys Sin 45: 593-600. doi: 10.1093/abbs/gmt049
  22. Hirota K, Yoshitomi H, Hashimoto M, Maeda S, Teradaira S, Sugimoto N, Yamaguchi T, Nomura T, Ito H, Nakamura T, Sakaguchi N, Sakaguchi N (2007) Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med 204: 2803-2812. doi: 10.1084/jem.20071397
  23. Liu Y, Lagowski JP, Gao S, Raymond JH, White CR, Kulesz-Martin MF (2010) Regulation of the psoriatic chemokine CCL20 by E3 ligases Trim32 and Piasy in keratinocytes. J Invest Dermatol 130: 1384-1390. doi: 10.1038/jid.2009.416
  24. Armstrong AW, Read C (2020) Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA 23: 1945-1960. doi:10.1001/jama.2020.4006
  25. Mare SD, Jong ED, Van de Kerkhof PCM (1990) DNA content and Ks8. 12 binding of the psoriatic lesion during treatment with the vitamin D3 nalogue MC903 and betamethasone. Br J Dermatol 123: 291-295. doi: 10.1111/j.1365-2133.1990.tb06287.x
  26. Ngamwonglumlert L, Devahastin S, Chiewchan N, Raghavan GV (2020) Color and molecular structure alterations of brazilein extracted from Caesalpinia sappan L. under different pH and heating conditions. Sci Rep 10: 1-10. doi: 10.1038/s41598-020-69189-3
  27. Nirmal NP, Rajput MS, Prasad RG, Ahmad M (2015) Brazilin from Caesalpinia sappan heartwood and its pharmacological activities: A review. Asian Pac J Trop Med 8: 421-430. doi: 10.1016/j.apjtm.2015.05.014
  28. Choi DH, Hwang HS (2019) Anti-inflammation activity of brazilin in TNF-α induced human psoriasis dermatitis skin model. Appl Biol Chem 62: 46. doi: 10.1186/s13765-019-0455-z
  29. Arican O, Aral M, Sasmaz S, Ciragil P (2005) Serum levels of TNF-α, IFN-γ, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm 2005: 273-279. doi: 10.1155/MI.2005.273
  30. 30Sano S (2015) Psoriasis as a barrier disease. Dermatologica Sinica 33: 64-69. doi: 10.1016/j.dsi.2015.04.010
  31. Roberson ED, Bowcock AM (2010) Psoriasis genetics: breaking the barrier. Trends Genet 26: 415-423. doi: 10.1016/j.tig.2010.06.006
  32. Toussirot E (2012) The IL23/Th17 pathway as a therapeutic target in chronic inflammatory diseases. Inflammation & Allergy-Drug Targets 11: 159-168. doi: 10.2174/187152812800392805
  33. Hawkes JE, Yan BY, Chan TC, Krueger JG (2018) Discovery of the IL23/IL-17 signaling pathway and the treatment of psoriasis. J Immunol 201: 1605-1613. doi: 10.4049/jimmunol.1800013
  34. Xie J, Huang S, Huang H, Deng X, Yue P, Lin J, Yang M, Han L, Zhang DK (2021) Advances in the application of natural products and the novel drug delivery systems for psoriasis. Front Pharmacol 12: 644952. doi: 10.3389/fphar.2021.644952
  35. Yuan H, Ma Q, Ye L, Piao G (2016) The traditional medicine and modern medicine form natural products. Molecules 21: 559. doi: 10.3390/molecules21050559
  36. Shim JH (2019) Anti-inflammatory effect of brazilin in RAW264. 7 cells. Asian J Beauty Cosmetol 17: 107-115. doi: 10.20402/ajbc.2019.0270