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

Ralph JA, Zocco D, Bresnihan B, Fitzgerald O, McEvoy AN, Murphy EP
Source: Am J Pathol
Publication Date: (2007)
Issue: 170(3): 1121-33
Research Area:
Cancer Research/Cell Biology
Dermatology/Tissue Engineering
Cells used in publication:
Endothelial, MV lung, human (HMVEC-L)
Species: human
Tissue Origin: lung
Synoviocyte, human
Species: human
Tissue Origin:
Nucleofector® I/II/2b
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.