1. ¹Department of Public Health and Clinical Medicine, Dermatology and Venereology, Umeå University, Umeå, Sweden
2. ²Department of Dermatology, University of Münster, Münster, Germany

Correspondence: Dr Maria Brattsand, Department of Public Health and Clinical Medicine, Dermatology and Venereology, Umeå University, Build 6M, 3rd floor, SE-901 85 Umeå, Sweden. E-mail: maria.brattsand@dermven.umu.se

Received 14 March 2007; Revised 7 May 2007; Accepted 17 May 2007; Published online 12 July 2007.

Abstract

Proteinase-activated receptor-2 (PAR₂) is a seven transmembrane spanning, G-protein-coupled receptor, present on the membrane of many cell types including keratinocytes. In skin, PAR₂ is suggested to play a regulatory role during inflammation, epidermal barrier function, and pruritus. PAR₂ is activated by trypsin-like proteases by a unique mechanism where cleavage of the receptor leads to the release of a small peptide, which activates the receptor as a tethered ligand. The endogenous activators of PAR₂ on keratinocytes have not been identified as of yet. Potential candidates are kallikrein-related peptidases (KLKs) expressed by epidermal cells. Therefore, the ability of four human skin-derived KLKs was examined with regard to their capacity to activate PAR₂ in vitro. PAR₂ cleavage was followed by immunofluorescence analysis and functional activation by measurements of changes in intracellular calcium levels. We found that KLK5 and KLK14, but neither KLK7 nor KLK8, induced PAR₂ signalling. We conclude that certain, but not all, epidermal KLKs are capable of activating PAR₂. We could also show the coexpression of KLK14 and PAR₂ receptor in inflammatory skin disorders. These in vitro results suggest that KLKs may take part in PAR₂ activation in the epidermis and thereby in PAR₂-mediated inflammatory responses, including epidermal barrier repair and pruritus. The role of KLKs in PAR₂ activation in vivo remains to be elucidated.