A role for type 1α corticotropin-releasing hormone receptors in mediating local changes in chronically inflamed tissue

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

Research output: Contribution to journalArticlepeer-review

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 1α in chronically inflamed synovial tissue (ST). Analysis of ST from an early arthritis patient cohort (n = 9) established that expression of CRH-R1α significantly (P < 0.03) colocalized with PECAM-1 and E-selectin expression in vivo. Freshly excised ST explants released a media to r(s) that acts to promote CRH-R1α mRNA to levels present in inflamed human synovium (n = 8). We tested the ability of conditioned medium and individual inflammatory mediators to modulate CRH-R1α expression. Histamine selectively induced the expression of CRH-R1α, and these effects were mediated through the histamine receptor type 1. Ectopic expression of CRH-R1α 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 κB transcriptional activity. CRH enhanced the expression of nitric-oxide syndiase (NOS III) to promote NO production from CRH-R1α-expressing cells. These data establish a role for CRH receptor-mediated responses in regulating vascular changes associated with chronic synovitis.

Original languageEnglish
Pages (from-to)1121-1133
Number of pages13
JournalAmerican Journal of Pathology
Volume170
Issue number3
DOIs
Publication statusPublished - Mar 2007
Externally publishedYes

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