Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.
Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1 Omura, Nagasaki, 856-8562, Japan.
BMC Immunol. 2020 Jun 15;21(1):35. doi: 10.1186/s12865-020-00365-w.
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.
先天免疫细胞通过释放细胞因子在类风湿关节炎（RA）的病理生理学中发挥关键作用。Janus 激酶（JAK）的小分子抑制剂在 RA 患者中具有临床疗效。然而，由于 JAK 与细胞因子受体形成异二聚体复合物，因此每种 JAKi 的同工型特异性作用难以评估。我们评估了几种 JAKi 对 GM-CSF 预刺激的人先天免疫细胞的影响。
在 THP-1 细胞中，JAKi（托法替尼、巴瑞替尼、乌帕替尼）在较高浓度（400 nM）下可预防 GM-CSF 诱导的 JAK2/STAT5 磷酸化。与巴瑞替尼或乌帕替尼相比，托法替尼在较低浓度（≤100 nM）下对 GM-CSF 诱导的 JAK2/STAT5 磷酸化的抑制作用较弱。所有 JAKi 均抑制 GM-CSF 诱导的人中性粒细胞产生 IL-1β。然而，与托法替尼或乌帕替尼相比，巴瑞替尼在较低浓度（≤100 nM）下对 IL-1β 产生的抑制作用更大。同样，所有 JAKi 均抑制 GM-CSF 诱导的人中性粒细胞产生 caspase-1（p20）。
我们得出结论，用 JAKi 孵育可防止 GM-CSF 介导的人先天免疫细胞中 JAK2/STAT5 的激活。虽然巴瑞替尼和乌帕替尼几乎完全阻断了 GM-CSF 介导的 JAK2/STAT5 信号通路，但托法替尼在较低浓度下的抑制作用较弱，这表明这些 JAKi 在抑制 JAK2 信号通路方面存在差异。
