title: Increased expression of cathelicidin by direct activation of protease-activated receptor 2: possible implications on the pathogenesis of rosacea.
abstract: OBJECTIVE
  Recent findings of increased cathelicidin protein and its proteolytic fragments in rosacea suggest a pathogenic role for cathelicidin in this disease. The relationship between cathelicidin and protease-activated receptor 2 (PAR-2) is therefore of 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 rosacea and to test the effect of direct PAR-2 activation on cathelicidin expression in keratinocytes.
  
  
  METHODS
  Samples from 40 patients with clinicopathologic diagnosis of rosacea and facial skin tissue samples from 20 patients with no specific findings or milium without inflammation were retrieved. Intensities of immunohistochemical staining for PAR-2 and cathelicidin were compared between normal and rosacea-affected skin tissues. Additionally, correlations between PAR-2 and cathelicidin staining intensities within rosacea patients were analyzed. In cultured keratinocytes, changes in PAR-2, cathelicidin, and vascular endothelial growth factor (VEGF) mRNA and protein were analyzed after treatment with PAR-2 activating peptide (AP).
  
  
  RESULTS
  Cathelicidin expression was significantly higher 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 cultured keratinocytes, compared with PAR-2 control peptide treatment.
  
  
  CONCLUSIONS
  PAR-2 may participate in the pathogenesis of rosacea through activation of cathelicidin LL-37, a mediator of innate immune responses in the skin.
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Yoon Jee
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Beom Jin
authors.initials: BJ
authors.lastname: Lim
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Sohn
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Shin
authors.affiliation: Department of Dermatology, Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. oddung93@yuhs.ac.
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Oh
mesh_terms: D000328:Adult; D000368:Aged; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D044464:Receptor, PAR-2 / Q000378:metabolism*; D012393:Rosacea / Q000473:pathology*; D012867:Skin / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D044464:Receptor, PAR-2; D042461:Vascular Endothelial Growth Factor A; D054804:Cathelicidins
keywords: Cathelicidin; LL-37; PAR-2; VEGF; rosacea