Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis

Objective. To examine the regulation and mode of action of peripheral corti cotropin-releasing hormone (CRH) in human inflammatory arthritis. Methods. CRH messenger RNA (mRNA) levels were measured in normal and inflam ed synovial tissue and in primary synoviocytes prior to and following cytok ine stimulation. Primary synoviocytes were transiently transfected with CRH promoter/reporter constructs, and promoter activity in response to cytokin es was assessed. Immunohistochemical staining established CRH receptor expr ession, and Northern blot analysis confirmed that the nuclear transcription factors NUR77 and NURR1 contributed to synovial CRH receptor-mediated sign aling. Primary synoviocytes were treated with pro- and antiinflammatory med iators, and the time course of NURR1. and NUR77 modulation was examined. Nu clear extracts were analyzed by electrophoretic mobility shift assay to det ermine NURR1 binding to the CRH promoter/enhancer. Results. CRH mRNA was up-regulated in the synovial tissue in rheumatoid art hritis (RA), psoriatic arthritis (PsA), and sarcoid arthritis, but not in n ormal synovium. Inflammatory cytokines, such as interleukin-1 beta and tumo r necrosis factor alpha, enhanced the transcriptional activity of the human CRH promoter and increased levels of CRH mRNA in primary synoviocytes. Syn ovial CRH functioned in a paracrine manner to induce NURR1 and NUR77. NURR1 was abundantly expressed in the inflammatory cells of both RA and PsA syno vium. NURR1 and NUR77 were differentially regulated, and NURR1 was the majo r cytokine-regulated member of the NURR subfamily as well as the mediator o f cytokine- and CRH-dependent inflammatory responses in synovium. Furthermo re, glucocorticoids dramatically suppressed cytokine- and CRH-induced synov ial NURR1 mRNA. Conclusion. These data demonstrate the involvement of the transcription fac tor NURR1 in the regulation of CRH expression and activity in human inflamm atory arthritis.