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