본문 바로가기
KERD
논문KCI 등재

Increased Expression of Cathelicidin by Direct Activation of Protease-Activated Receptor 2: Possible Implications on the Pathogenesis of Rosacea

2

조회

0

다운로드

1

인용

0

참고문헌

키워드

주제분류의학일반

초록

Purpose: Recent findings of increased cathelicidin protein and its proteolytic fragmentsin rosacea suggest a pathogenic role for cathelicidin in this disease. The relationshipbetween cathelicidin and protease-activated receptor 2 (PAR-2) is thereforeof interest, as PAR-2, expressed principally in keratinocytes, regulates pro-inflammatory cytokine expression in the skin. The purpose of this study was to determine the relationship between expression of PAR-2 and cathelicidin in rosaceaand to test the effect of direct PAR-2 activation on cathelicidin expression in keratinocytes. Materials and Methods: Samples from 40 patients with clinicopathologicdiagnosis of rosacea and facial skin tissue samples from 20 patients with no specific findings or milium without inflammation were retrieved. Intensitiesof immunohistochemical staining for PAR-2 and cathelicidin were compared between normal and rosacea-affected skin tissues. Additionally, correlations betweenPAR-2 and cathelicidin staining intensities within rosacea patients were analyzed. In cultured keratinocytes, changes in PAR-2, cathelicidin, and vascular endothelialgrowth factor (VEGF) mRNA and protein were analyzed after treatment with PAR-2 activating peptide (AP). Results: Cathelicidin expression was significantlyhigher in rosacea skin tissues than in normal tissues (p<0.001), while PAR-2 expression was not significantly higher in rosacea tissues than in normal skin tissues. A positive correlation between PAR-2 and cathelicidin within rosacea samples was observed (R=0.330, p=0.037). After treatment of PAR-2 AP, both mRNA and protein levels for PAR-2, cathelicidin, and VEGF significantly increased in culturedkeratinocytes, compared with PAR-2 control peptide treatment. Conclusion: PAR-2 may participate in the pathogenesis of rosacea through activation of cathelicidinLL-37, a mediator of innate immune responses in the skin.

Abstract

Purpose: Recent findings of increased cathelicidin protein and its proteolytic fragmentsin rosacea suggest a pathogenic role for cathelicidin in this disease. The relationshipbetween cathelicidin and protease-activated receptor 2 (PAR-2) is thereforeof interest, as PAR-2, expressed principally in keratinocytes, regulates pro-inflammatory cytokine expression in the skin. The purpose of this study was to determine the relationship between expression of PAR-2 and cathelicidin in rosaceaand to test the effect of direct PAR-2 activation on cathelicidin expression in keratinocytes. Materials and Methods: Samples from 40 patients with clinicopathologicdiagnosis of rosacea and facial skin tissue samples from 20 patients with no specific findings or milium without inflammation were retrieved. Intensitiesof immunohistochemical staining for PAR-2 and cathelicidin were compared between normal and rosacea-affected skin tissues. Additionally, correlations betweenPAR-2 and cathelicidin staining intensities within rosacea patients were analyzed. In cultured keratinocytes, changes in PAR-2, cathelicidin, and vascular endothelialgrowth factor (VEGF) mRNA and protein were analyzed after treatment with PAR-2 activating peptide (AP). Results: Cathelicidin expression was significantlyhigher in rosacea skin tissues than in normal tissues (p<0.001), while PAR-2 expression was not significantly higher in rosacea tissues than in normal skin tissues. A positive correlation between PAR-2 and cathelicidin within rosacea samples was observed (R=0.330, p=0.037). After treatment of PAR-2 AP, both mRNA and protein levels for PAR-2, cathelicidin, and VEGF significantly increased in culturedkeratinocytes, compared with PAR-2 control peptide treatment. Conclusion: PAR-2 may participate in the pathogenesis of rosacea through activation of cathelicidinLL-37, a mediator of innate immune responses in the skin.

참고문헌 (41)

  1. Korting HC, "Current topical and systemic approaches to treatment of rosacea", J Eur Acad Dermatol Venereol, 23, pp.876~882 (2009)
  2. Wilkin J, "Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea", J Am Acad Dermatol, 46, pp.584~587 (2002)
  3. Yamasaki K, "Rosacea as a disease of cathelicidins and skin innate immunity", J Investig Dermatol Symp Proc, 15, pp.12~15 (2011)
  4. Nizet V, "Innate antimicrobial peptide protects the skin from invasive bacterial infection", Nature, 414, pp.454~457 (2001)
  5. Zanetti M, "The role of cathelicidins in the innate host defenses of mammals", Curr Issues Mol Biol, 7, pp.179~196 (2005)
  6. Koczulla R, "An angiogenic role for the human peptide antibiotic LL-37", hCAP-18, 2003, pp.111, 1665~1672
  7. Braff MH, "Structure-function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities", J Immunol, 174, pp.4271~4278 (2005)
  8. Yamasaki K, "Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea", Nat Med, 13, pp.975~980 (2007)
  9. Yamasaki K, "Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin", FASEB J, 20, pp.2068~2080 (2006)
  10. Detmar M, "Overexpression of vascular permeability factor", vascular endothelial growth factor and its receptors in psoriasis, 1994, pp.180, 1141~1146
  11. Hansen KK, "Proteinases, proteinase-activated receptors (PARs) and the pathophysiology of cancer and diseases of the cardiovascular, musculoskeletal, nervous and gastrointestinal systems", Naunyn Schmiedebergs Arch Pharmacol, 377, pp.377~392 (2008)
  12. Coughlin SR, "Protease-activated receptors start a family", Proc Natl Acad Sci U S A, 91, pp.9200~9202 (1994)
  13. Rattenholl A, "Proteinase-activated receptor-2 in the skin: receptor expression, activation and function during health and disease", Drug News Perspect, 21, pp.369~381 (2008)
  14. Stefansson K, "Activation of proteinase-activated receptor-2by human kallikrein-related peptidases", J Invest Dermatol, 128, pp.18~25 (2008)
  15. Chung WO, "Protease-activated receptor signaling increases epithelial antimicrobial peptide expression", J Immunol, 173, pp.5165~5170 (2004)
  16. Lee SE, "Protease-activated receptor-2 mediates the expression of inflammatory cytokines, antimicrobial peptides, and matrix metalloproteinases in keratinocytes in response to Propionibacterium acnes", Archives of Dermatological Research, 302(10), pp.745~756 (2010)
  17. Elewski BE, "A comparison of 15%azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial", Arch Dermatol, 139, pp.1444~1450 (2003)
  18. Crawford GH, "Rosacea: I. Etiology, pathogenesis, and subtype classification", J Am Acad Dermatol, 51, pp.327~341 (2004)
  19. Neumann E, "Capillaropathy and capillaroneogenesis in the pathogenesis of rosacea", Int J Dermatol, 37, pp.263~266 (1998)
  20. Lacey N, "Mite-related bacterial antigens stimulate inflammatory cells in rosacea", Br J Dermatol, 157, pp.474~481 (2007)
  21. McAleer MA, "Papulopustular rosacea:prevalence and relationship to photodamage", J Am Acad Dermatol, 63, pp.33~39 (2010)
  22. Selsted ME, "Mammalian defensins in the antimicrobial immune response", Nat Immunol, 6, pp.551~557 (2005)
  23. Zaiou M, "Cathelicidins, essential gene-encoded mammalian antibiotics", J Mol Med (Berl), 80, pp.549~561 (2002)
  24. Schröder JM, "Human beta-defensin-2", Int J Biochem Cell Biol, 31, pp.645~651 (1999)
  25. Murakami M, "Cathelicidin anti-microbial peptide expression in sweat, an innate defense system for the skin", J Invest Dermatol, 119, pp.1090~1095 (2002)
  26. Wu WK, "Cathelicidins in inflammation and tissue repair: potential therapeutic applications for gastrointestinal disorders", Acta Pharmacol Sin, 31, pp.1118~1122 (2010)
  27. Davidson DJ, "The cationic antimicrobial peptide LL-37 modulates Yonsei Med J http:", J Immunol, pp.2004, 172[DOI]
  28. Zaiou M, "Antimicrobial and protease inhibitory functions of the human cathelicidin (hCAP18", LL-37) prosequence, 2003, pp.120, 810~816
  29. Steinmann J, "Phenylbutyrate induces antimicrobial peptide expression", Antimicrob Agents Chemother, 53, pp.5127~5133 (2009)
  30. Gombart AF, "Regulation of the CAMP gene by 1,25(OH)2D3 in various tissues", J Steroid Biochem Mol Biol, 103, pp.552~557 (2007)
  31. Yim S, "Induction of cathelicidin in normal and CF bronchial epithelial cells by 1,25-dihydroxyvitamin D(3)", J Cyst Fibros, 6, pp.403~410 (2007)
  32. White JH, "Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future", J Steroid Biochem Mol Biol, 121, pp.234~238 (2010)
  33. Kawabata A, "PAR-2: structure, function and relevance to human diseases of the gastric mucosa", Expert Rev Mol Med, 4, pp.1~17 (2002)
  34. Sondell B, "Immunolocalization of stratum corneum chymotryptic enzyme in human skin and oral epithelium with monoclonal antibodies: evidence of a proteinase specifically expressed in keratinizing squamous epithelia", J Histochem Cytochem, 42, pp.459~465 (1994)
  35. Hachem JP, "Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity", J Invest Dermatol, 125, pp.510~520 (2005)
  36. Buddenkotte J, "Agonists of proteinase-activated receptor-2stimulate upregulation of intercellular cell adhesion molecule-1 in primary human keratinocytes via activation of NF-kappa B", J Invest Dermatol, 124, pp.38~45 (2005)
  37. Wakita H, "Thrombin and trypsin induce granulocyte-macrophage colony-stimulating factor and interleukin-6 gene expression in cultured normal human keratinocytes", Proc Assoc Am Physicians, 109, pp.190~207 (1997)
  38. Hou L, "Immunolocalization of protease-activated receptor-2 in skin:receptor activation stimulates interleukin-8 secretion by keratinocytes in vitro", Immunology, 94, pp.356~362 (1998)
  39. Kawagoe J, "Effect of protease-activated receptor-2 deficiency on allergic dermatitis in the mouse ear", Jpn J Pharmacol, 88, pp.77~84 (2002)
  40. Gruber BL, "Protease-activated receptor-2 (PAR-2) expression in human fibroblasts is regulated by growth factors and extracellular matrix", J Invest Dermatol, 123, pp.832~839 (2004)
  41. Xiang Y, "Expression of proteinase-activated receptors (PAR)-2 in articular chondrocytes is modulated by IL-1beta, TNFalpha and TGF-beta", Osteoarthritis Cartilage, 14, pp.1163~1173 (2006)

관련 논문AI추천

A Study on Vitamin D and Cathelicidin Status in Patients with Rosacea: Serum Level and Tissue Expression강희정, 고성훈, 김광중, 김광호, 박복원, 박은주, 박혜림, 조은별, 진재광, 하지민대한피부과학회 · Annals of Dermatology2018 · 제30권 제2호The Effect of Capsaicin on Neuroinflammatory Mediators of Rosacea김현빈, 나의영, 윤숙정, 이지범대한피부과학회 · Annals of Dermatology2022 · 제34권 제4호Hyaluronan Oligosaccharides Improve Rosacea-Like Phenotype through Anti-Inflammatory and Epidermal Barrier-Improving Effects김동현, 신정우, 윤문수, 이선구, 이희정대한피부과학회 · Annals of Dermatology2020 · 제32권 제3호Protease-Activated Receptor-2 Is Associated with Terminal Differentiation of Epidermis and Eccrine Sweat Glands고영권, 김창덕, 김현우, 김형원, 박진운, 신용섭, 이영호, 이증훈, 정성균대한피부과학회 · Annals of Dermatology2015 · 제27권 제4호The Anti-Angiogenic Effect of Microbotox on Rosacea Is Due to the Suppressed Secretion of VEGF by Mast Cells Resulting From Internalization of the MRGPRX2 ReceptorDong Bing-Qi, Geng Meng-Meng, Lei Tie-Chi, Le Yue, Liao Zhi-Kai, Liu Lin-Xia, Wan Jing대한피부과학회 · Annals of Dermatology2025 · 제37권 제4호Citron Essential Oils Alleviate the Mediators Related to Rosacea Pathophysiology in Epidermal Keratinocytes나의영, 윤숙정, 이승철, 이지범, 전현우대한피부과학회 · Annals of Dermatology2018 · 제30권 제6호

이 간행물의 다른 논문 (20건)