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(American Journal of Pathology. 2007;170:1121-1133.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061000

A Role for Type 1 Corticotropin-Releasing Hormone Receptors in Mediating Local Changes in Chronically Inflamed Tissue

Jennifer A. Ralph^*, Davide Zocco^*, Barry Bresnihan, Oliver FitzGerald, Alice N. McEvoy^* and Evelyn P. Murphy^*

From the College of Life Sciences, Veterinary Sciences Centre,^* St. Vincent’s University Hospital, Elm Park; and the Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland

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 1 in chronically inflamed synovial tissue (ST). Analysis of ST from an early arthritis patient cohort (n = 9) established that expression of CRH-R1 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-R1 mRNA to levels present in inflamed human synovium (n = 8). We tested the ability of conditioned medium and individual inflammatory mediators to modulate CRH-R1 expression. Histamine selectively induced the expression of CRH-R1, and these effects were mediated through the histamine receptor type 1. Ectopic expression of CRH-R1 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 B transcriptional activity. CRH enhanced the expression of nitric-oxide synthase (NOS III) to promote NO production from CRH-R1-expressing cells. These data establish a role for CRH receptor-mediated responses in regulating vascular changes associated with chronic synovitis.

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