Sang Eun Lee, et al. tion, inhibition of PAR-2 activation, by topical application of either serine protease inhibitor or PAR-2 specific anta- gonist significantly accelerated the barrier recovery rate after acute barrier disruption.65 These results implicates that PAR-2 activation might be an important signal for regulat- ing LB secretion during the repair response after barrier disruption. While serine protease/PAR-2 signaling negati- vely affects permeability barrier homeostasis by inhibiting the restoration of lipid barrier (mortar), it could also act as a positive regulator in the permeability barrier recovery by accelerating cornification, which then induces the forma- tion of corneocytes (bricks) (Fig. 2).11 Recent studies have demonstrated that proteolytically active allergens, house dust mites and cockroaches, also activated PAR-2 and delayed barrier recovery via PAR-2 signal-mediated inhibi- tion of LB secre-tion.12 By showing the abnormal distribu- tion of calcium ions after barrier disruption in skin where allergens had been applied, the authors suggest that PAR-2 signaling-mediated modulation of calcium ions in the skin could be one of the mechanisms involved in the regulation of LB secretion by PAR-2.12 Inflammation The role of PAR-2 in the regulation of inflammation has been widely investigated. During cutaneous inflammation, potential endogenous activators of PAR-2, including leuko- cyte elastase, mast cell tryptase, proteinases of the trypsin- family produced by keratinocytes (trypsinogen-4), and proteinases of the fibrinolysis cascade such as factor VII/Xa, are released; these then activate PAR-2 on keratinocytes, endothelial cells, inflammatory cells, and dermal sensory nerves to amplify the inflammation via the up-regulation of inflammatory mediators.66 It has been demonstrated that PAR-2 agonist peptide induces intercellular adhesion mole- cule-1 (ICAM-1) expression in primary human keratino- cytes via the activation of nuclear factor-kappa B.67 Another study reported that stimulation of PAR-2 on keratinocytes increased the secretion of interleukin (IL)-6 and granulo- cyte-macrophage colony-stimulating factor (GM-CSF).68 In keratinocytes, PAR-2 activation also leads to a secretion of IL-8/CXCL8, promoting granulocyte and T-cell recruit- ment.69 The observation that PAR-2 deficient mice show diminished ear swelling and inflammatory infiltrates in a model of contact hypersensitivity indicates that PAR-2 mediates inflammation in allergic dermatitis.70 In addition, PAR-2 has been observed at increased levels in lesional skin of patients with AD, suggesting that PAR-2 plays a role in inflammatory dermatosis.15,17 In addition to these proinflammatory responses, PAR-2 also has been shown to be involved in the T-helper type 2 (Th2) mediated aller- gic inflammation. Thymic stromal lymphopoietin (TSLP), a Th2-associated cytokine produced by inflammatory cells as well as epithelial cells, is known to induce Th2 cell recruitment and allergic inflammation via dendritic cell stimulation in response to allergen challenge, microbial infections, and inflammation.71 TSLP transgenic mouse has been shown to develop an AD-like skin disease, which suggests an important role of TSLP in initiating and per- petuating Th2 immune responses in AD.72,73 A recent study reported that SPINK5 knockout mice expressed TSLP in the epidermis at a higher rate than that of wild-type epider- mis, and demonstrated that KLK5 directly activates PAR-2, which in turn induces nuclear factor κB-mediated over- expression of TSLP. This implies that LEKTI defici-ency- induced serine protease/PAR-2 activation triggers proin- flammatory as well as proallergic inflammatory res-ponses in the development of AD-like phenotype of NS (Fig. 3).74 Pruritus Skin nerve fibers are known to have functional PAR-2, Fig. 4. Proteases and PAR-2 in the pathogenesis of atopic dermatitis. LETKI, lympho-epithelial Kazal-type-related inhibitor; PAR-2, protease- activated receptor-2; SCCE, stratum corneum chymotrypsin-like enzyme; SCTE, stratum corneum trypsin-like enzyme; SNP, single nucleotide polymorphism. 814 Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010