| Popis: |
Background: Rheumatoid arthritis (RA) is influenced by the activity of the sympathetic nervous system (SNS). In animal models of RA, the SNS promotes severity of the disease and its manipulation modulates experimental arthritis depending on timing of the intervention. Synovial fibroblasts (SF) are major contributors to RA pathology but their modulation by the SNS has been rarely investigated. In this study we assessed the expression and function of adrenergic receptors in RA and osteoarthritis (OA) synovial fibroblasts and investigated their downstream signaling. Methods: We used western blot and quantitative PCR (qPCR) to determine protein and mRNA of adrenergic receptors in OASF/RASF. Furthermore we determined α1a and β2 protein in synovial tissue by immunofluorescence. ELISA was employed to determine IL-6 production. p38 kinase activation and translocation was analyzed by cell-based ELISA and immunofluorescence.Results: We detected α1a, α2b, β1, β2 and β3 protein in OASF/RASF and α1a and β2 protein in synovial tissue of OA and RA patients. The pro-inflammatory cytokines IFN-γ and TNF downregulated β3 adrenergic receptor. Activation of α1a, α2b, β2 and β3 increased production of TNF-induced IL-6 which was inhibited by specific antagonists. Furthermore, β3 agonism enhanced p38 phosphorylation and translocation to the nucleus.Conclusion: Among a comprehensive characterization of the adrenergic system of OASF/ RASF, we report for the first time β3 expression and demonstrated that this adrenergic receptor participates in the inflammatory response of synovial fibroblasts. Therefore, modulation of β3 might pose a new therapeutic opportunity to modulate synovial fibroblast function in patients with RA. |
