Review Article DOI 10.3349/ymj.2010.51.6.808 pISSN: 0513-5796, eISSN: 1976-2437 Yonsei Med J 51(6):808-822, 2010 Protease and Protease-Activated Receptor-2 Signaling in the Pathogenesis of Atopic Dermatitis Sang Eun Lee,1,2 Se Kyoo Jeong,3 and Seung Hun Lee1,2 1Department of Dermatology, 2Human Barrier Research Institute, Yonsei University College of Medicine, Seoul; 3Research Division, NeoPharm Co., Ltd., Daejeon, Korea. Received: August 17, 2010 Corresponding author: Dr. Seung Hun Lee, Department of Dermatology, Yonsei University College of Medicine, Gangnam Severance Hospital, 712 Eonju-ro, Gangnam-gu, Seoul 135-720, Korea. Tel: 82-2-2019-3361, Fax: 82-2-3463-6136 E-mail: ydshderm@yuhs.ac ∙The authors have no financial conflicts of interest. Proteases in the skin are essential to epidermal permeability barrier homeostasis. In addition to their direct proteolytic effects, certain proteases signal to cells by activating protease-activated receptors (PARs), the G-protein-coupled receptors. The expression of functional PAR-2 on human skin and its role in inflammation, pruritus, and skin barrier homeostasis have been demonstrated. Atopic dermatitis (AD) is a multifactorial inflammatory skin disease characterized by genetic barrier defects and allergic inflammation, which is sustained by gene-environmental interactions. Recent studies have revealed aberrant expression and activation of serine proteases and PAR-2 in the lesional skin of AD patients. The imbalance between proteases and protease inhibitors associated with genetic defects in the protease/protease inhibitor encoding genes, increase in skin surface pH, and exposure to proteolytically active allergens contribute to this aberrant protease/ PAR-2 signaling in AD. The increased protease activity in AD leads to abnormal desquamation, degradation of lipid-processing enzymes and antimicrobial peptides, and activation of primary cytokines, thereby leading to permeability barrier dysfunction, inflammation, and defects in the antimicrobial barrier. Moreover, up-regulated proteases stimulate PAR-2 in lesional skin of AD and lead to the production of cytokines and chemokines involved in inflammation and immune responses, itching sensation, and sustained epidermal barrier perturbation with easier allergen penetration. In addition, PAR-2 is an important sensor for exogenous danger molecules, such as exogenous proteases from various allergens, and plays an important role in AD pathogenesis. Together, these findings suggest that protease activity or PAR-2 may be a future target for therapeutic intervention for the treatment of AD. Key Words: Atopic dermatitis, protease, protease-activated receptor-2 (PAR-2) INTRODUCTION © Copyright: Yonsei University College of Medicine 2010 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non- Commercial License (http://creativecommons.org/ licenses/by-nc/3.0) which permits unrestricted non- commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Proteases are now considered not only to be enzymes that conduct hydrolysis of peptide bonds linking amino acids, but also signaling molecules that play an important role in homeostatic regulation in mammals and numerous pathological conditions.1,2 In the skin, three families of proteases have been found in the stratum corneum (SC), including the epidermal specific serine proteases, kallikrein 5 (SC tryptic enzyme, SCTE) and kallikrein 7 (SC chymotryptic enzyme, SCCE), as well as cysteine proteases, including cathepsin C, L, and V (SC thiol protease), 808 Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010