IL-22/IL-22R1 axis and S100A8/A9 alarmins in human osteoarthritic and rheumatoid arthritis synovial fibroblasts
IL-22/IL-22R1 axis and S100A8/A9 alarmins in human osteoarthritic and rheumatoid arthritis synovial fibroblasts
复制标题
DOI：
10.1093/rheumatology/ket315
复制
发表时间：
2013-12-01
期刊：
影响因子：
5.5
通讯作者：
Gomariz, Rosa P.
中科院分区：
文献类型：
--
作者：
Carrion, Mar;Juarranz, Yasmina;Gomariz, Rosa P.
目标.成纤维细胞样滑膜细胞（FLS）在风湿性疾病滑膜炎的发病机制中起着至关重要的作用。靶向FLS激活代表了开发治疗策略的方法。我们的目的是研究炎症关节的微环境是否可以调节IL-22和IL-22 R1在OA和RA FLS上的表达。我们还研究了IL-22对FLS活化以及对它们的IL-17相关反应的影响。通过RT-PCR和免疫印迹研究IL-22和IL-22 R1的表达。通过ELISA试剂盒测量增殖。RT-PCR检测IL-17受体、p19 IL-23和alarmins。通过流式细胞术评估IL-17受体表达。ELISA法检测MMP 1和IL-23。免疫荧光法和ELISA法检测S100 A8/A9的表达。使用基于细胞的ELISA试剂盒定量信号转导和转录激活因子3（STAT 3）磷酸化。IL-22和IL-22 R1在FLS中组成型表达。我们证明了S100 A8和S100 A9是在FLS中合成的。我们报道了炎症介质增加IL-22/IL-22 R1轴的表达，放大FLS激活。IL-22促进FLS增殖，上调MMP 1和S100 A8/A9的产生。IL-22可诱导STAT 3磷酸化，阻断JAK 2和JAK 3活性后，IL-22对S100 A8/A9的刺激作用减弱。IL-22对RA FLS中IL-23和IL-17 RC的表达有抑制作用，对OA FLS中IL-17 RA有抑制作用。基于IL-22的药理学破坏信号传导的疗法可能有益于治疗风湿性疾病。IL-22 R1对非淋巴细胞的限制性表达可导致免疫应答介导的副作用的减少。
Objectives. Fibroblast-like synoviocytes (FLSs) are crucial players in the pathogenesis of synovitis in rheumatic diseases. Targeting FLS activation represents an approach to the development of therapeutic strategies. Our aim was to investigate whether the microenvironment of inflamed joints could modulate the expression of IL-22 and IL-22R1 on OA and RA FLSs. We also examined the effect of IL-22 on FLS activation as well as on their IL-17-related responses.Methods. IL-22 and IL-22R1 expression was studied by RT-PCR and immunoblotting. Proliferation was measured by an ELISA kit. IL-17 receptors, p19IL-23 and alarmins were analysed by RT-PCR. IL-17 receptor expression was evaluated by flow cytometry. MMP1 and IL-23 were measured by ELISA. S100A8/A9 expression was detected by immunofluorescence and ELISA. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was quantified using a cell-based ELISA kit.Results. IL-22 and IL-22R1 were expressed constitutively in FLSs. We demonstrated that S100A8 and S100A9 were synthesized in FLSs. We reported that inflammatory mediators increased the expression of the IL-22/IL-22R1 axis, amplifying FLS activation. IL-22 enhanced FLS proliferation and up-regulated MMP1 and S100A8/A9 production. STAT3 phosphorylation was induced after IL-22 treatment and the stimulatory effect of IL-22 on S100A8/A9 was reduced after the activities of Janus kinase 2 (JAK2) and JAK3 were blocked. We showed an inhibitory action of IL-22 on IL-23 and IL-17RC expression in RA FLSs and on IL-17RA in OA FLSs.Conclusion. Therapies based on the pharmacological disruption signalling of IL-22 could be beneficial for the treatment of rheumatic diseases. The restricted expression of IL-22R1 to non-lymphoid cells could lead to a reduction of side effects mediated by immune responses.