Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines. Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA. However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors. We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells. Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400 nM) in THP-1 cells. Whereas compared with baricitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations (≤ 100 nM). All JAKi inhibited GM-CSF-induced IL-1β production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1β production were larger compared to those of tofacitinib or upadacitinib at lower concentrations (≤ 100 nM). Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils. We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells. Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi in the inhibition of JAK2 signaling pathways.

中文翻译：

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JAK抑制剂会破坏先天免疫细胞中GM-CSF介导的信号传导。

通过释放细胞因子，先天免疫细胞在类风湿关节炎（RA）的病理生理中起着至关重要的作用。Janus激酶（JAKi）的小分子抑制剂在RA患者中临床有效。但是，由于每个JAKs与细胞因子受体形成异二聚体复合物，因此每个JAKi的同工型特异性作用都难以评估。我们评估了几种JAKi对GM-CSF引发的人类先天免疫细胞的影响。用JAKi（托法替尼，baricitinib，upadacitinib）治疗可防止THP-1细胞中GM-CSF诱导的JAK2 / STAT5磷酸化水平更高（400 nM）。与baricitinib或upadacitinib相比，tofacitinib对GM-CSF诱导的JAK2 / STAT5磷酸化的抑制作用在较低浓度（≤100 nM）时较弱。所有JAKi均抑制人嗜中性粒细胞诱导GM-CSF诱导的IL-1β产生。但是，在较低浓度（≤100 nM）下，与tofacitinib或upadacitinib相比，baricitinib对IL-1β产生的抑制作用更大。同样，所有JAKi均抑制人嗜中性粒细胞诱导GM-CSF诱导的caspase-1（p20）的产生。我们得出结论，与JAKi孵育可防止人先天免疫细胞中GM-CSF介导的JAK2 / STAT5激活。尽管baricitinib和upadacitinib几乎完全阻断了GM-CSF介导的JAK2 / STAT5信号传导，但tofacitinib在较低浓度下的抑制作用较弱，这表明这些JAKi在抑制JAK2信号通路中存在变异。所有JAKi均抑制人嗜中性粒细胞产生GM-CSF诱导的caspase-1（p20）。我们得出结论，与JAKi孵育可防止人先天免疫细胞中GM-CSF介导的JAK2 / STAT5激活。尽管baricitinib和upadacitinib几乎完全阻断了GM-CSF介导的JAK2 / STAT5信号传导，但tofacitinib在较低浓度下的抑制作用较弱，这表明这些JAKi在抑制JAK2信号通路中存在变异。所有JAKi均抑制人嗜中性粒细胞产生GM-CSF诱导的caspase-1（p20）。我们得出结论，与JAKi孵育可防止人先天免疫细胞中GM-CSF介导的JAK2 / STAT5激活。尽管baricitinib和upadacitinib几乎完全阻断了GM-CSF介导的JAK2 / STAT5信号传导，但tofacitinib在较低浓度下的抑制作用较弱，这表明这些JAKi在抑制JAK2信号通路中存在变异。