Interleukin-17- and protease-activated receptor 2-mediated production of CXCL1 and CXCL8 modulated by cyclosporine A, vitamin D3 and glucocorticoids in human keratinocytes.
Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor which mediates a variety of functions in the skin including cutaneous inflammation. SLIGKV-NH(2) , an agonist peptide for PAR2, enhanced the interleukin (IL)-17-induced production of two CXC chemokines, CXCL1 (GRO-α) and CXCL8 (IL-8), in normal human epidermal keratinocytes (NHEK) in a concentration-dependent manner. The enhanced production of those chemokines was suppressed by a PAR2-specific siRNA. The SLIGKV-NH(2) -induced production of both CXCL1 and CXCL8 was markedly reduced by cyclosporine A. The enhanced production of CXCL1 was suppressed by 1α, 24R-dihydroxyvitamin D(3) , an active form of vitamin D(3) , and weakly by glucocorticoids, dexamethasone and clobetasol propionate, whereas production of CXCL8 was not altered by any of those receptor agonists. In psoriatic skin, the thickened upper spinous layer of the epidermis was positive for PAR2 protein and the expression of the IL17A mRNA was increased. These results suggest that the IL-17-induced pro-inflammatory reaction is enhanced by the activation of PAR2 in keratinocytes, and that the effect of PAR2 is differentially modulated by cyclosporine A, the active form of vitamin D(3)  and glucocorticoids.
Department of Dermatology, Hyogo College of Medicine, Hyogo, Japan.
Ryoko
R
Takei-Taniguchi
Yasutomo
Y
Imai
Chika
C
Ishikawa
Yoshiko
Y
Sakaguchi
Noboru
N
Nakagawa
Tatsuya
T
Tsuda
Morley D
MD
Hollenberg
Kiyofumi
K
Yamanishi
D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000096:biosynthesis*; D002990:Clobetasol / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004100:Dihydroxycholecalciferols / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis*; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D011565:Psoriasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D044464:Receptor, PAR-2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C475829:CXCL1 protein, human; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D004100:Dihydroxycholecalciferols; D005938:Glucocorticoids; C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17; D016209:Interleukin-8; D009842:Oligopeptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044464:Receptor, PAR-2; C515807:seryl-leucyl-isoleucyl-glycyl-lysyl-valinamide; C023850:1 alpha,24-dihydroxyvitamin D3; D003907:Dexamethasone; D016572:Cyclosporine; D002990:Clobetasol