The antimicrobial protein S100A7/psoriasin enhances the expression of keratinocyte differentiation markers and strengthens the skin's tight junction barrier.
BACKGROUND
S100A7/psoriasin is a member of the S100 protein family and is encoded in the epidermal differentiation complex, which contains genes for markers of epidermal differentiation. S100A7/psoriasin is overexpressed in hyperproliferative skin diseases, where it is believed not only to exhibit antimicrobial functions, but also to induce immunomodulatory activities, including chemotaxis and cytokine/chemokine production.


OBJECTIVE
To evaluate the effect of S100A7/psoriasin on keratinocyte differentiation and regulation of the tight junction (TJ) barrier.


METHODS
Expression of differentiation markers and TJ proteins in human keratinocytes was determined by real-time polymerase chain reaction and Western blot. The changes in TJ barrier function were assessed by transepithelial electrical resistance and paracellular permeability assays. Glycogen synthase kinase-3 (GSK-3) and mitogen-activated protein kinase (MAPK) activation was analysed by Western blot, whereas β-catenin and E-cadherin activation was evaluated by Western blot and immunofluorescence.


RESULTS
S100A7/psoriasin enhanced the expression of several differentiation markers and selectively increased the expression of TJ proteins (e.g. claudins and occludin), which are known to strengthen the TJ barrier. Furthermore, S100A7/psoriasin increased β-catenin and E-cadherin accumulation at cell-cell contact, and enhanced transepithelial electrical resistance while reducing the paracellular permeability of keratinocyte layers. The data suggest that S100A7/psoriasin-mediated regulation of the TJ barrier was via both the GSK-3 and MAPK pathways, as evidenced by the inhibitory effects of inhibitors for GSK-3 and MAPKs.


CONCLUSIONS
Our finding that S100A7/psoriasin regulates differentiation and strengthens TJ barrier function provides novel evidence that, in addition to antimicrobial and immunoregulatory activities, S100A7/psoriasin is involved in skin innate immunity.
Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan; Mikimoto Pharmaceutical, Mie, Japan.
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F
Hattori
C
C
Kiatsurayanon
K
K
Okumura
H
H
Ogawa
S
S
Ikeda
K
K
Okamoto
F
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Niyonsaba
D000943:Antigens, Differentiation / Q000187:drug effects*; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D003911:Dextrans / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects*; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
D000943:Antigens, Differentiation; D015820:Cadherins; D003911:Dextrans; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D062725:Tight Junction Proteins; D051176:beta Catenin; C015219:fluorescein isothiocyanate dextran; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D020929:Mitogen-Activated Protein Kinase Kinases; D016650:Fluorescein-5-isothiocyanate