Abstract
Stratum corneum tryptic enzyme kallikrein 5 (KLK5) is a serine protease that is involved in the cell renewal and maintenance of the skin barrier function. The excessive activation of KLK5 causes an exacerbation of dermatoses, such as rosacea and atopic dermatitis. Some triterpenoids are reported to suppress the serine proteases. We aimed to investigate whether bioactive triterpenoids modulate the KLK5 protease. Nineteen triterpenoids occurring in medicinal crude drugs were evaluated using an enzymatic assay to measure the anti-KLK5 activity. The KLK5-dependent cathelicidin peptide LL-37 production in human keratinocytes was examined using immunoprecipitation and Western blotting. Screening assays for evaluating the anti-KLK5 activity revealed that ursolic acid, oleanolic acid, saikosaponin b1, tumulosic acid and pachymic acid suppressed the KLK5 protease activity, although critical molecular moieties contributing to anti-KLK5 activity were unclarified. Ursolic acid and tumulosic acid suppressed the proteolytic processing of LL-37 in keratinocytes at ≤10 μM; no cytotoxicity was observed. Both triterpenoids were detected in the plasma of rats administered orally with triterpenoid-rich crude drug Jumihaidokuto. Our study reveals that triterpenoids, such as ursolic acid and tumulosic acid, modulate the KLK5 protease activity and cathelicidin peptide production. Triterpenoids may affect the skin barrier function via the regulation of proteases.
Highlights
Stratum corneum tryptic enzyme kallikrein 5 (KLK5) is a serine protease that is expressed in the epidermis and is involved in the cell renewal and maintenance of skin barrier function.KLK5 plays a central role in the degradation of corneodesmosome, which is the main adhesive structure in the cornified cell layer
We further investigated the selectivity of triterpenoids against the KLK5 protease activity using two representative triterpenoids: ursolic acid out of pentacyclic triterpenoids, and tumulosic acid two representative triterpenoids: acid out of pentacyclic tumulosic acid out out of tetracyclic triterpenoids.ursolic
[5], our findings suggest that ursolic acid and tumulosic acid regulate the proteolytic processing of KLK5 and modulate Cathelicidin antimicrobial peptides (CAMPs) production in keratinocytes
Summary
Stratum corneum tryptic enzyme kallikrein 5 (KLK5) is a serine protease that is expressed in the epidermis and is involved in the cell renewal and maintenance of skin barrier function.KLK5 plays a central role in the degradation of corneodesmosome, which is the main adhesive structure in the cornified cell layer. Stratum corneum tryptic enzyme kallikrein 5 (KLK5) is a serine protease that is expressed in the epidermis and is involved in the cell renewal and maintenance of skin barrier function. KLK5 is involved in the activation of other epithelial serine proteases such as kallikrein- and matriptase-family protease [1,2]. Lympho-epithelial Kazal-type inhibitor 1 (LEKTI-1), an endogenous inhibitor of serine protease, was shown to regulate KLK5 and the family proteases in healthy humans [3,4]. In Netherton syndrome, which is caused by loss-of-function mutations in SPINK5 encoding for LEKTI, an aberrant KLK5 protease activity in patients with this syndrome causes extensive skin desquamation, inflammation, allergic manifestations, and hair shaft defects [4]
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