Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase.
Proteinase-activated receptor-2 (PAR-2) is a G-protein coupled receptor. Tryptic proteases cleave PAR-2 exposing a tethered ligand (SLIGKV), which binds and activates the receptor. Although PAR-2 is highly expressed by cultured keratinocytes and is an inflammatory mediator, its precise localization in the normal and inflamed human skin is unknown, and the proteases that activate PAR-2 in the skin have not been identified. We localized PAR-2 in human skin by immunohistochemistry, examined PAR-2 expression by RT-PCR and RNA blotting, and investigated PAR-2 activation by mast cell tryptase. PAR-2 was localized to keratinocytes, especially in the granular layer, to endothelial cells, hair follicles, myoepithelial cells of sweat glands, and dermal dendritic-like cells. PAR-2 was also highly expressed in keratinocytes and endothelial cells of inflamed skin. PAR-2 mRNA was detected in normal human skin by RT-PCR, and in cultured human keratinocytes and dermal microvascular endothelial cells by Northern hybridization. Trypsin, tryptase and a peptide corresponding to the tethered ligand (SLIGKVNH2) increased [Ca2+]i in keratinocytes, measured using Fura-2/AM. Although tryptase-containing mast cells were sparsely scattered in the normal dermis, they were numerous in the dermis in atopic dermatitis, and in the dermis, dermal-epidermal border, and occasionally within the lower epidermis in psoriasis. Tryptase may activate PAR-2 on keratinocytes and endothelial cells during inflammation.
Steinhoff
M
M
Department of Surgery, University of California, San Francisco, USA.
Corvera
C U
CU
Thoma
M S
MS
Kong
W
W
McAlpine
B E
BE
Caughey
G H
GH
Ansel
J C
JC
Bunnett
N W
NW
D001692:Biological Transport / Q000502:physiology; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D053818:Chymases; D003876:Dermatitis, Atopic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000502:physiology*; D008407:Mast Cells / Q000201:enzymology*; D008833:Microcirculation / Q000502:physiology; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000378:metabolism / Q000502:physiology*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D012867:Skin / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution / Q000502:physiology; D053802:Tryptases
D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D012697:Serine Endopeptidases; C083294:chymase 2; D053818:Chymases; D053802:Tryptases; D002118:Calcium