title: Agonists of proteinase-activated receptor 2 induce cytokine release and activation of nuclear transcription factor kappaB in human dermal microvascular endothelial cells.
abstract: Proteinase-activated receptor 2 belongs to a new G protein-coupled receptor subfamily activated by various serine proteases. It has been demonstrated to play a role during inflammation of many tissues including the skin. Proteinase-activated receptor 2 is expressed by endothelial cells and regulates cutaneous inflammation in vivo. The underlying mechanisms of proteinase-activated receptor 2 activation in the skin and the effects on human dermal microvascular endothelial cells, however, are still unknown. Agonists of proteinase-activated receptor 2 such as mast cell tryptase induce widespread inflammation in many organs including the skin. Trypsinogen is generated by endothelial cells during inflammation or tumor growth. Therefore we tested whether human dermal microvascular endothelial cells express functional proteinase-activated receptor 2 and whether agonists of proteinase-activated receptor 2 regulate inflammatory responses in these cells. Calcium mobilization studies revealed that proteinase-activated receptor 2 is functional in human dermal microvascular endothelial cells. Interleukin-6 and interleukin-8 were upregulated as detected by reverse transcription polymerase chain reaction or enzyme-linked immunosorbent assay indicating a role of proteinase-activated receptor 2 in stimulating human dermal microvascular endothelial cells. Electromobility shift assays revealed proteinase-activated-receptor-2-induced activation of nuclear transcription factor kappaB with a maximum after 1 h. In conclusion, agonists of proteinase-activated receptor 2 upregulate interleukin-6 and interleukin-8 expression and release in human dermal microvascular endothelial cells. Thus, proteinase-activated receptor 2 may play an important role in cutaneous inflammation by mediating inflammatory responses on dermal microvascular endothelial cells and activation of nuclear transcription factor kappaB.
authors.affiliation: Department of Dermatology and Ludwig Boltzmann Institute for Cell- and Immunbiology of the Skin, University of Münster, Germany.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Shpacovitch
authors.forename: Thomas
authors.initials: T
authors.lastname: Brzoska
authors.forename: Jörg
authors.initials: J
authors.lastname: Buddenkotte
authors.forename: Christoph
authors.initials: C
authors.lastname: Stroh
authors.forename: Christian P
authors.initials: CP
authors.lastname: Sommerhoff
authors.forename: John C
authors.initials: JC
authors.lastname: Ansel
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Luger
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008833:Microcirculation; D016328:NF-kappa B / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists*; D012867:Skin / Q000098:blood supply*; D014357:Trypsin / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D009842:Oligopeptides; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D014357:Trypsin