Ortiz M A, Diaz-Torné C, Hernández M V, Reina D, de la Fuente D, Castellví I, Moya P, Ruiz J M, Corominas H, Zamora C, Cantó E, Sanmartí R, Juarez C, Vidal S
IIB-Institut Recerca Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
Unit of Rheumatology, Department of Internal Medicine, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
Clin Immunol. 2015 Jun;158(2):174-82. doi: 10.1016/j.clim.2015.03.025. Epub 2015 Apr 3.
Considering the interplay of multiple STATs in response to cytokines, we investigated how IL-6 and its blocking affect STAT signaling in rheumatoid arthritis (RA). Leukocytes obtained from RA patients before and after tocilizumab treatment and healthy donors (HDs) were cytokine-stimulated and STAT phosphorylation was analyzed by cytometry. RA patients had significantly fewer pSTAT1+, pSTAT3+, and pSTAT6+ monocytes and pSTAT5+ lymphocytes than HDs. After 24weeks of treatment, percentages of IFNγ-induced pSTAT1+ and IL-10-induced pSTAT3+ monocytes in RA patients increased, reaching levels comparable to HDs. pSTAT1+ and pSTAT3+ cells correlated inversely with RA disease activity index and levels of pSTAT+ cells at baseline were higher in patients with good EULAR response to tocilizumab. IFNγ-induced pSTAT1+ cells correlated inversely with memory T cells and anti-CCP levels. IL-10-induced pSTAT3+ cells correlated with Treg/Teff ratio. Our findings suggest that IL-6 blocking reduces the inflammatory mechanisms through the correction of STAT1 and STAT3 activation status.
考虑到多种信号转导和转录激活因子（STATs）在细胞因子应答中的相互作用，我们研究了白细胞介素-6（IL-6）及其阻断作用如何影响类风湿关节炎（RA）中的STAT信号传导。对托珠单抗治疗前后的RA患者以及健康供体（HDs）获取的白细胞进行细胞因子刺激，并通过细胞术分析STAT磷酸化情况。与HDs相比，RA患者中磷酸化信号转导和转录激活因子1（pSTAT1+）、磷酸化信号转导和转录激活因子3（pSTAT3+）以及磷酸化信号转导和转录激活因子6（pSTAT6+）单核细胞和磷酸化信号转导和转录激活因子5（pSTAT5+）淋巴细胞明显更少。治疗24周后，RA患者中干扰素γ（IFNγ）诱导的pSTAT1+单核细胞和白细胞介素-10（IL-10）诱导的pSTAT3+单核细胞百分比增加，达到与HDs相当的水平。pSTAT1+和pSTAT3+细胞与RA疾病活动指数呈负相关，对托珠单抗有良好欧洲抗风湿病联盟（EULAR）反应的患者基线时pSTAT+细胞水平更高。IFNγ诱导的pSTAT1+细胞与记忆T细胞和抗环瓜氨酸肽（anti-CCP）水平呈负相关。IL-10诱导的pSTAT3+细胞与调节性T细胞/效应性T细胞（Treg/Teff）比值相关。我们的研究结果表明，IL-6阻断通过纠正STAT1和STAT3激活状态来减少炎症机制。
