Repression of interferon β-regulated cytokines by the JAK1/2 inhibitor ruxolitinib in inflammatory human macrophages
Repression of interferon β-regulated cytokines by the JAK1/2 inhibitor ruxolitinib in inflammatory human macrophages
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DOI：
10.1016/j.intimp.2017.11.032
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发表时间：
2018-01-01
影响因子：
5.6
通讯作者：
Fardel, Olivier
中科院分区：
文献类型：
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作者：
Febvre-James, Marie;Lecureur, Valerie;Fardel, Olivier
Ruxolitinib是Janus激酶（JAK）1/2抑制剂，目前用于治疗骨髓增生性肿瘤。它发挥有效的抗炎活性，但涉及的分子和细胞机制仍然知之甚少。为了获得关于这一点的见解，在人巨噬细胞中研究了鲁索利替尼对主要炎性细胞因子表达的影响，巨噬细胞构成了与炎症有关的关键细胞类型。通过PCR阵列分析细胞因子（n = 84）的mRNA表达表明，在由促炎刺激脂多糖（LPS）（n = 44）诱导的细胞因子中，61.4%（n = 27）被5 μ M ruxolitinib抑制。ruxolitinib在mRNA和蛋白水平上显著下调了主要的炎性细胞因子白细胞介素（IL）6和肿瘤坏死因子α。其他受抑制的细胞因子包括1127和趋化因子CCL 2、CXCL 9、CXCL 10和CXCL 11，但不包括IL 1 β。干扰素（IFN）β/JAK/信号转导子和转录激活子（STAT）途径，如通过IFN β和STAT 1磷酸化的分泌增加以及参考IIN β-应答基因的上调所证明的，在人巨噬细胞中被LPS充分激活，同时被JAK抑制剂阻断。Ruxolitinib靶向的大多数细胞因子显示出以JAK敏感的方式被IFN β调节。此外，使用针对IFN β受体的阻断性单克隆抗体抵消IFN β/JAK/STAT级联导致与JAK抑制剂反应中观察到的细胞因子抑制特征相似的细胞因子抑制特征。总体而言，这些数据提供了鲁索利替尼通过抑制LPS/IFN β/JAK/STAT信号通路介导的人巨噬细胞中炎性细胞因子抑制的证据，这可能有助于JAK抑制剂的抗炎作用。
Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor, currently used in the treatment of myeloproliferative neoplasms. It exerts potent anti-inflammatory activity, but the involved molecular and cellular mechanisms remain poorly understood. In order to gain insights about this point, ruxolitinib effects towards expression of main inflammatory cytokines were studied in human macrophages, which constitute a key-cell type implicated in inflammation. Analysis of mRNA expression of cytokines (n = 84) by PCR array indicated that, among those induced by the pro-inflammatory stimulus lipopolysaccharide (LPS) (n = 44), 61.4% (n = 27) were repressed by 5 mu M ruxolitinib. The major inflammatory cytokines, interleukin (IL) 6 and tumor necrosis factor alpha, were notably down-regulated by ruxolitinib at both the mRNA and protein level. Other repressed cytokines included 1127 and the chemokines CCL2, CXCL9, CXCL10 and CXCL11, but not IL1 beta. The interferon (IFN)beta/JAK/signal transducer and activator of transcription (STAT) pathway, well-activated by LPS in human macrophages as demonstrated by increased secretion of IFN beta&STAT1 phosphorylation, and up-regulation of reference IIN beta-responsive genes, was concomitantly blocked by the JAK inhibitor. Most of cytokines targeted by ruxolitinib were shown to be regulated by IFN beta in a JAK-sensitive manner. In addition, counteracting the IFN beta/JAK/STAT cascade using a blocking monoclonal antibody directed against IFN beta receptor resulted in a similar profile of cytokine repression to that observed in response to the JAK inhibitor. Overall, these data provide evidence for ruxolitinib-mediated repression of inflammatory cytokines in human macrophages through inhibition of the LPS/IFN beta/JAK/STAT signalling pathway, which probably contributes to the anti-inflammatory effects of the JAK inhibitor.