title: A role for type 1alpha corticotropin-releasing hormone receptors in mediating local changes in chronically inflamed tissue.
abstract: Peripheral corticotropin-releasing hormone (CRH) is an important regulator of localized inflammatory responses. The aim of this study is to define the pathological signaling pathways in which peripheral CRH receptor-mediated responses reside. We report that PECAM-1-expressing synovial membrane endothelial cells are the principal source of CRH receptor subtype 1alpha in chronically inflamed synovial tissue (ST). Analysis of ST from an early arthritis patient cohort (n = 9) established that expression of CRH-R1alpha significantly (P < 0.03) colocalized with PECAM-1 and E-selectin expression in vivo. Freshly excised ST explants released a mediator(s) that acts to promote CRH-R1alpha mRNA to levels present in inflamed human synovium (n = 8). We tested the ability of conditioned medium and individual inflammatory mediators to modulate CRH-R1alpha expression. Histamine selectively induced the expression of CRH-R1alpha, and these effects were mediated through the histamine receptor type 1. Ectopic expression of CRH-R1alpha in normal human endothelial and synoviocyte cells resulted in the induction of the orphan receptor NR4A2 through the reconstitution of cAMP/protein kinase A/cAMP response element-binding protein signaling and identified a role for CRH in modulating nuclear factor kappaB transcriptional activity. CRH enhanced the expression of nitric-oxide synthase (NOS III) to promote NO production from CRH-R1alpha-expressing cells. These data establish a role for CRH receptor-mediated responses in regulating vascular changes associated with chronic synovitis.
authors.affiliation: College of Life Sciences, Veterinary Sciences Centre, University College Dublin, Belfield, Dublin, Ireland..
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Ralph
authors.forename: Davide
authors.initials: D
authors.lastname: Zocco
authors.forename: Barry
authors.initials: B
authors.lastname: Bresnihan
authors.forename: Oliver
authors.initials: O
authors.lastname: Fitzgerald
authors.forename: Alice N
authors.initials: AN
authors.lastname: McEvoy
authors.forename: Evelyn P
authors.initials: EP
authors.lastname: Murphy
mesh_terms: D001168:Arthritis / Q000378:metabolism / Q000473:pathology; D015152:Blotting, Northern; D015139:Blotting, Southern; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D004268:DNA-Binding Proteins; D019040:E-Selectin; D016328:NF-kappa B; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D000099052:CRF Receptor, Type 1; D006632:Histamine; D050882:CREB-Binding Protein