Study on the mechanism for the production of CXCR3-agonisitic chemokines by synovial fibroblasts from patients with rheumatoid arthritis

类风湿关节炎（RA）的炎症滑膜组织以Th1细胞浸润为特征，Th1细胞主要表达趋化因子受体CXCR3和CCRS。在这项研究中，我们研究了来自RA患者的滑膜组织细胞和滑膜成纤维细胞系（第四或第五代）产生CXCR3激动性趋化因子CXCL9、CXCL10和CXCL11。RA患者滑液中所有CXCR3配体浓度明显高于骨关节炎（OA）患者。与OA患者的细胞相比，RA患者的滑膜组织细胞更强烈地表达CXCR3配体mrna，并自发分泌更多的这些趋化因子蛋白。干扰素-γ (IFN-γ)、肿瘤坏死因子-α (TNF-α)或白细胞介素-1β (IL-1β)刺激后，RA患者滑膜成纤维细胞中所有CXCR3配体的mRNA表达均被诱导。然而，IFN-γ刺激后，滑膜成纤维细胞显著分泌CXCL9和CXCL10蛋白，而不分泌CXCL11蛋白，TNF-α或IL-1β刺激后仅分泌CXCL10蛋白。当用IFN-γ和TNF-α联合刺激时，这些细胞能够分泌大量的这三种趋化因子。这些结果表明，滑膜成纤维细胞可能通过产生Th1相关趋化因子CXCR3配体参与Th1免疫应答的延续，IFN-γ和TNF-α的协同作用可能对RA关节趋化因子的产生很重要。

The inflamed synovial tissue of rheumatoid arthritis (RA) is characterized by an infiltration with Th1 cells that predominantly express the chemokine receptors CXCR3 and CCRS. In this study, we investigated the production of the CXCR3 agonistic chemokines CXCL9, CXCL10, and CXCL11 by synovial tissue cells and synovial fibroblast-cell lines (forth or fifth passage) from RA patients. Concentrations of all CXCR3 ligands in synovial fluids were markedly higher in RA patients than in osteoarthritis (OA) patients. Synovial tissue cells from RA patients more strongly expressed mRNAs for CXCR3 ligands and spontaneously secreted larger amounts of these chemokine proteins, compared with the cells from OA patients. The mRNA expression of all CXCR3 ligands was induced in synovial fibroblasts from RA patients after stimulation with interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), or interleukin-1β (IL-1β). However, synovial fibroblasts significantly secreted CXCL9 and CXCL10 proteins, but not CXCL11 protein, after IFN-γ stimulation, and secreted only CXCL10 protein after TNF-α or IL-1β stimulation. When stimulated with a combination of IFN-γ and TNF-α, these cells were able to secrete large amounts of all three chemokines. These results indicate that synovial fibroblasts may be involved in perpetuating the Th1 immune response by producing the Th1-associated chemokines CXCR3 ligands, and the synergistic effect of IFN-γ and TNF-α may be important for their chemokine production in RA joints.