inhibit KLK5, -6, -7, -13, and -14.31 LEKTI-1 is stored in specific intracellular LB cargoes, separated from the KLKs, until it is secreted and released into the SC-SG junction to colocalize with KLK5 and KLK7 and inhibit their activity. The interaction strength between LEKTI-1 and KLKs is regulated by the SC pH gradient, with its highest inhibitory capacity at a neutral pH and decreased activity in an acidic pH environment, such as in the superficial SC layer. This implies that a normal SC pH gradient regulates the controlled release of active KLKs in the superficial SC layer and prevents premature desqua- mation in the deep SC layer, where the pH is neutral.34 These findings support the fact that AD, characterized by altered skin surface pH, and NS, characterized by geneti- cally defective LEKTI, display similar phenotypic features, including premature and excessive desquamation. Recen- tly, LEKTI-2, the product of SPINK9, has been identified to be focally localized at the SG and SC at palmar and plantar sites in close proximity to KLK5.35 It was found that recombinant LEKTI-2 inhibited KLK5 but not KLK7 and -14, suggesting that LEKTI-2 contributes to the regulation of the desquamation process by inhibiting KLK5 pro- teolytic activity. Other serine protease inhibitors and their roles are summarized in Table 1.36-38 PAR-2 IN SKIN PAR is a G-protein coupled receptor, characterized by a unique mechanism of self-activation following specific Table 1. Serine Proteases and Their Inhibitor in Skin Serine protease inhibitor Genes Lymphoepithelial Kazal- type-related inhibitor-1 (LEKTI-1) LEKTI-2 Alpha-2 macroglobulin- like 1 (α2ML1)37 Secretory leukocyte protease inhibitor (SLPI)/Elafin Hepatocyte growth factor activator inhibitor 1 (HAI-1)38,39 SC, stratum corneum. Sang Eun Lee, et al. proteolytic cleavage of their extracellular domains.39 Until now, four PAR members have been identified. PAR-1, -3, and -4 are known to be activated by thrombin, and thereby involved in homeostasis and thrombosis, whereas PAR-2 is activated by trypsin-like serine proteases, but not by thrombin.10,40 PAR-2 is known to be widely distributed throughout the mammalian body. In the skin, PAR-2 is abundantly expressed by almost all cell types, especially by keratinocytes. In addition, endothelial cells, fibroblasts, sensory neurons, and inflammatory cells such as mast cells, T lymphocytes, eosinophils, neutrophils, monocytes, macrophages, and dendritic cells are also reported to ex- press functional PAR-2.10,40 Previous studies demonstrated that PAR-2 was expressed in the suprabasal layers of both human and murine epidermis, and that this expression was most prominent in the granular layer, implying that PAR-2 expression might depend on the state of epidermal differ- entiation.7,40 As opposed to normal skin, the lesional skin of atopic dermatitis has been shown to express high levels of PAR-2 also in the lower epidermal layers.21,40,41 PAR-2 as well as KLK14 has been shown to be widely distributed in lesional skin in rosacea, another inflammatory skin disease.21 Taken together, this evidence suggests that PAR- 2 expression may be induced by cutaneous inflammation. In addition, PAR-2 expression has been reported to be re- gulated by ultraviolet irradiation and involved in melano- some transfer.42 Various endogenous serine proteases including trypsin, mast cell derived tryptase, KLK5, -6, and, -14, matriptase- 1 [membrane-type serine protease-1 (MT-SP1)], human Function or disease association Netherton syndrome Hyperkeratotic hand and foot eczema Regulation of desquamation by limiting the bioavailability of KLK7 in the SC Antimicrobial defense in the skin Matriptase transport and activation Serine protease inhibitor Kazal-type5 (SPINK5) SPINK 9 A2ML1 Target proteases Trypsin, plasmin, subtilisin A, cathepsin G, human neutrophil elastase, KLK5, -6, -7, -13, -14 KLK5 KLK7, papain, subtilisin Trappin gene family Neutrophil serine proteases Serine protease inhibitor Kunitz type 1 (SPINT1) gene Matriptase (probably prostatin) 810 Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010