STAT-6-mediated control of P-selectin by substance P and interleukin-4 in human dermal endothelial cells.
P-Selectin expressed on endothelial cells contributes to acute and chronic inflammation by promoting leukocyte tethering/rolling. Despite increasing evidence of P-selectin expression on human umbilical vein endothelial cells in vitro, the regulatory mechanisms of P-selectin expression on dermal endothelial cells in skin diseases are not fully understood. Here, we demonstrate increased expression of P-selectin in dermal vessels of regional skin in urticaria and atopic dermatitis. The present in vitro analyses with human dermal microvascular endothelial cells (HDMECs) revealed that histamine rapidly induced P-selectin expression. Interleukin (IL)-4 and IL-13 induced prolonged expression of surface P-selectin by HDMECs. A combination of tumor necrosis factor-alpha and IL-4 inhibited P-selectin expression. Pretreatment of HDMECs with tumor necrosis factor-alpha followed by incubation with IL-4 markedly increased P-selectin expression. Notably, incubation with substance P alone induced prolonged P-selectin expression. Activation of STAT6 appears to be a key factor in P-selectin expression induced by substance P and IL-4 because treatment with STAT6 decoy oligodeoxynucleotides significantly inhibited P-selectin expression. The present results indicate that novel, complex mechanisms are involved in endothelial P-selectin expression in the skin. STAT6 in dermal endothelial cells appears to be a potent target for controlling cellular infiltrate in allergic and/or neuroinflammatory skin diseases.
Miyazaki
Yasuhiro
Y
Department of Dermatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Japan.
Satoh
Takahiro
T
Nishioka
Kiyoshi
K
Yokozeki
Hiroo
H
D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D016384:Consensus Sequence; D020405:Dermis / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D019007:P-Selectin / Q000378:metabolism*; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D012871:Skin Diseases / Q000473:pathology; D013373:Substance P / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019007:P-Selectin; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D013373:Substance P