The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels
The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels
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DOI：
10.1093/rheumatology/keu430
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发表时间：
2015-06-01
期刊：
影响因子：
5.5
通讯作者：
Silvennoinen, Olli
中科院分区：
文献类型：
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作者：
Isomaki, Pia;Junttila, Ilkka;Silvennoinen, Olli
Objective.参与RA的许多细胞因子激活Janus激酶-信号转导子和转录激活子（JAK-STAT）通路。抑制这些途径的治疗药物正在开发用于RA。为了研究RA中JAK-STAT通路活性的疾病相关改变，我们研究了STAT 1和STAT 3在未刺激和阿托伐他汀刺激的细胞中的表达和活化，并测定了循环细胞因子的水平。采用RT-PCR方法检测RA患者和健康志愿者外周血（PB）、SF T细胞和单核细胞中STAT 1和STAT 3 mRNA的表达。使用多色流式细胞术分析PB T细胞和单核细胞中基础和细胞因子（IFN-γ、IL-6、IL-10）诱导的STAT磷酸化。RA患者外周血T细胞和单核细胞中STAT 3 mRNA水平均上调。STAT 1在SF单核细胞中表达升高。RA患者静息PB T细胞和单核细胞中磷酸化STAT 3的水平显著高于健康志愿者。RA患者血浆中IL-6水平升高，并与CD 4（+）T细胞和单核细胞中STAT 3磷酸化水平相关。IL-6介导的STAT 3活化在RA患者的T细胞中失调。在高血浆IL-6水平和组成性STAT 3磷酸化患者的CD 4（+）T细胞中，IL-6诱导的STAT 3磷酸化降低。结果表明，IL-6诱导活动性RA中循环免疫细胞中STAT 3的过度活化，随后使T细胞中的IL-6应答脱敏。
Objective. Many cytokines involved in RA activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Therapeutic drugs that inhibit these pathways are being developed for RA. To investigate disease-related alterations in the activity of JAK-STAT pathways in RA, we studied the expression and activation of STAT1 and STAT3 in unstimulated and cytokine-stimulated cells and determined the levels of circulating cytokines.Methods. The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and SF T cells and monocytes was studied in RA patients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-gamma, IL-6, IL-10)-induced STAT phosphorylation was analysed in PB T cells and monocytes using multicolour flow cytometric analysis.Results. STAT3 mRNA levels were up-regulated in both PB and SF T cells and monocytes from RA patients. STAT1 expression was elevated in SF monocytes. The levels of phospho-STAT3 in resting PB T cells and monocytes were significantly higher in patients with RA than in healthy volunteers. IL-6 levels were elevated in RA plasma and correlated with the level of STAT3 phosphorylation in CD4(+) T cells and monocytes. IL-6-mediated STAT3 activation was deregulated in T cells from RA patients. IL-6-induced phosphorylation of STAT3 was decreased in CD4(+) T cells from patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation.Conclusion. The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells.