Elevated levels of corticotropin-releasing hormone (CRH) are produced locally in inflamed human synovial tissue, and previous observations indicate a role for CRH in the pathogenesis of inflammatory joint disease. To further elucidate the biologic role of CRH at peripheral sites, we examined the expression of known CRH receptor subtypes in inflamed human synovium and compared the expression patterns in normal synovium.Immunohistochemical analysis was used to confirm enhanced expression of specific CRH receptor subtypes in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) synovium. Immunofluorescence double-labeling was used to further characterize CRH receptor-expressing cells. Reverse transcriptase-polymerase chain reaction analysis was performed to examine CRH receptor subtype messenger RNA (mRNA) expression in RA, PsA, and normal synovial tissue. In addition, CRH receptor expression was examined in isolated synovial endothelial cells and synoviocytes.Selective up-regulation of CRH receptors in inflamed synovial tissue indicated that CRH functions locally, in an autocrine/paracrine receptor-mediated manner. Immunoreactive CRH receptor type 1 (CRH-R1) was expressed abundantly on vascular endothelial cells and discrete perivascular cell populations, identified as mast cells. In all samples of inflamed synovium studied, CRH-R1alpha mRNA was detected; however, we were unable to identify CRH-R1beta or any CRH-R2 isoforms in samples from the same cohort of, patients. CRH receptor subtype expression in separated synovial cell populations revealed a pattern of staining similar to that seen in vivo. In contrast, neither CRH receptor subtype was expressed in normal synovial tissue.Our findings suggest that CRH signaling, via CRH-R1alpha, may play a role in both the vascular changes and the pathologic mechanisms associated with joint inflammation in human arthritis.