A role for type 1α 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 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. Copyright © American Society for Investigative Pathology.