Increased stratum corneum serine protease activity in acute eczematous atopic skin

Voegeli, R.; Rawlings, A. V.; Breternitz, Maria; Doppler, S.; Schreier, Thomas; Fluhr, Joachim W.

doi:10.1111/j.1365-2133.2009.09142.x

Cited by 165 publications

(188 citation statements)

References 41 publications

(56 reference statements)

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“…Thymic stromal lymphopoietin-activated human dendritic cells produce Th2-attracting chemokines, but no IL-12, and induce naïve CD4 ϩ and CD8 ϩ T cell differentiation into effector cells with a typical pro-allergic phenotype (33). Increased trypsin-like proteolytic activity was reported in atopic dermatitis lesions (34), which might be the result of decreased SPINK6 expression as demonstrated herein. As SPINK6 is a very potent and selective inhibitor of KLKs, it could have therapeutic potential to modulate increased KLK activity.…”

Section: Discussionsupporting

confidence: 69%

“…Kazal-like domains of LEKTI, the amino acid sequence of LEKTI domain 6 was used as a query to blast against the human genome (NCBI builder 34,2003). A gene locus was identified and localized between the two known genes, SPINK5 (GenBank TM accession number NM_001127698) and SPINK7 (accession number NM_032566) (Fig.…”

Section: Spink6 Is Expressed In Human Skin-to Search For Genes Encodimentioning

confidence: 99%

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Isolation of SPINK6 in Human Skin

Meyer‐Hoffert

Kantyka

et al. 2010

Journal of Biological Chemistry

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Kallikrein-related peptidases (KLKs) play a central role in skin desquamation. They are tightly controlled by specific inhibitors, including the lymphoepithelial Kazal-type inhibitor (LEKTI) encoded by SPINK5 and LEKTI-2 encoded by SPINK9. Herein, we identify SPINK6 as a selective inhibitor of KLKs in the skin. Unlike LEKTI but similar to LEKTI-2, SPINK6 possesses only one typical Kazal domain. Its mRNA was detected to be expressed at low levels in several tissues and was induced during keratinocyte differentiation. Natural SPINK6 was purified from human plantar stratum corneum extracts. Immunohistochemical analyses revealed SPINK6 expression in the stratum granulosum of human skin at various anatomical localizations and in the skin appendages, including sebaceous glands and sweat glands. SPINK6 expression was decreased in lesions of atopic dermatitis. Using KLK5, KLK7, KLK8, KLK14, thrombin, trypsin, plasmin, matriptase, prostasin, mast cell chymase, cathepsin G, neutrophil elastase, and chymotrypsin, inhibition with recombinant SPINK6 was detected only for KLK5, KLK7, and KLK14, with apparent K i values of 1.33, 1070, and 0.5 nM, respectively. SPINK6 inhibited desquamation of human plantar callus in an ex vivo model. Our findings suggest that SPINK6 plays a role in modulating the activity of KLKs in human skin. A selective inhibition of KLKs by SPINK6 might have therapeutic potential when KLK activity is elevated.The skin protects us from water loss and mechanical damage. The surface-exposed epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes, is most important for the barrier defense against these challenges. Recent discoveries have highlighted the balance of proteases and protease inhibitors as key players in both desquamation processes and epidermal barrier functions (1).Human tissue kallikreins, or kallikrein-related peptidases (KLKs), 3 are the largest family of trypsin-or chymotrypsin-like secreted serine proteases, which are encoded by 15 genes on chromosome region 19q13.4 (2). At least eight KLKs are expressed in normal skin, among which KLK5, KLK7, KLK8, and KLK14 have been reported to be most important (3-6). KLKs are capable of cleaving corneodesmosomes (7-10) and are thought to be key regulators of the desquamation process. The activity of KLKs is regulated by pH and specific protease inhibitors. The importance of epithelial protease inhibitors has been revealed impressively in Netherton syndrome (OMIM 256500), an autosomal recessive disorder caused by mutations in the gene SPINK5 (serine protease inhibitor Kazal-type 5) (11). Netherton syndrome presents as an ichthyosiform dermatosis with variable erythroderma, hair shaft defects (bamboo hair), atopic features, and growth retardation (12). Lymphoepithelial Kazal-type inhibitor (LEKTI) (13), the product of SPINK5, includes in its primary structure 15 different serine protease inhibitory domains (13). Domains 15 and 2 each comprise a typical Kazal-type structure, whereas the other domains lack a disu...

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Section: Discussionsupporting

confidence: 69%

Section: Spink6 Is Expressed In Human Skin-to Search For Genes Encodimentioning

confidence: 99%

Isolation of SPINK6 in Human Skin

Meyer‐Hoffert

Kantyka

et al. 2010

Journal of Biological Chemistry

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“…These lines of evidence suggest that KLK7 is a physiological activator of caspase-14. In some skin diseases such as AD, Netherton syndrome, and psoriasis (32)(33)(34), KLKs including KLK7 are up-regulated in the lesional epidermis. On the other hand, quantification of total caspase-14 and active caspase-14 in AD skin in our previous work clearly showed marked decreases of procaspase-14 and active caspase-14 in extracts from both nonlesional and lesional skin (35).…”

Section: Discussionmentioning

confidence: 99%

Kallikrein-related Peptidase-7 Regulates Caspase-14 Maturation during Keratinocyte Terminal Differentiation by Generating an Intermediate Form

Yamamoto

Miyai

Matsumoto

et al. 2012

Journal of Biological Chemistry

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“…The physiological pH of around 5.5 already results in more than 90% less active compared to optimal in vitro conditions. Patients with atopic dermatitis often show an elevated pH at the skin surface, which might likely contribute to observed elevated serine protease levels in these patients (Voegeli et al 2009). …”

Section: Other Regulating Factors Of Protease Activitymentioning

confidence: 99%

Epidermal Serine Proteases and Their Inhibitors in Atopic Dermatitis

Meyer‐Hoffert¹

2012

Atopic Dermatitis - Disease Etiology and Clinical Management

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Increased stratum corneum serine protease activity in acute eczematous atopic skin

Cited by 165 publications

References 41 publications

Isolation of SPINK6 in Human Skin

Isolation of SPINK6 in Human Skin

Kallikrein-related Peptidase-7 Regulates Caspase-14 Maturation during Keratinocyte Terminal Differentiation by Generating an Intermediate Form

Epidermal Serine Proteases and Their Inhibitors in Atopic Dermatitis

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