A JAK1 Selective Kinase Inhibitor and Tofacitinib Affect Macrophage Activation and Function
A JAK1 Selective Kinase Inhibitor and Tofacitinib Affect Macrophage Activation and Function
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DOI：
10.1093/ibd/izy364
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发表时间：
2019-04-01
影响因子：
4.9
通讯作者：
Wildenberg, M. E.
中科院分区：
文献类型：
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作者：
De Vries, L. C. S.;Duarte, J. M.;Wildenberg, M. E.
背景：Janus激酶（JAK）介导炎症性肠病中涉及的细胞因子信号传导。泛JAK抑制剂托法替尼已显示出治疗溃疡性结肠炎的疗效。然而，由于其广谱抑制作用而引起的不良事件的担忧推动了开发选择性JAK抑制剂的努力。鉴于骨髓细胞在肠道免疫稳态中的关键作用，我们评估了泛JAK和选择性JAK抑制剂对促炎和抗炎巨噬细胞极化和功能（M1/M2）以及实验性结肠炎的影响。（JAK 1 i; JAK 3 i）和托法替尼，并通过转录、功能和代谢分析进行评价。在体内，JAK 1 i和托法替尼（10或30 mg/kg）口服给药在急性和急性救援葡聚糖硫酸钠（DSS）colis.Results：托法替尼和JAK 1 i，但不JAK 3 i有效抑制STAT 1磷酸化和干扰素γ诱导的转录在M1极化的巨噬细胞。引人注目的是，转录谱表明从M1型到M2型巨噬细胞的转换，这得到了M2相关标志物蛋白表达增加的支持。此外，这两种抑制剂增强氧化磷酸化速率。在体内，JAK 1 i和托法替尼并没有保护小鼠免受急性DSS诱导的结肠炎，但改善恢复体重减轻和疾病活动在急性救援DSS诱导的结肠炎在最高dose.Conclusion：JAK 1 i和托法替尼，但不JAK 3 i诱导抗炎巨噬细胞的表型和功能特性，这表明JAK 1作为主要的效应途径托法替尼在这些细胞。在体内，JAK 1 i和托法替尼适度影响急性补救DSS诱导的结肠炎。
Background: Janus kinases (JAKs) mediate cytokine signaling involved in inflammatory bowel disease. The pan-JAK inhibitor tofacitinib has shown efficacy in the treatment of ulcerative colitis. However, concerns regarding adverse events due to their wide spectrum inhibition fueled efforts to develop selective JAK inhibitors. Given the crucial role of myeloid cells in intestinal immune homeostasis, we evaluated the effect of pan-JAK and selective JAK inhibitors on pro-and anti-inflammatory macrophage polarization and function (M1/M2) and in experimental colitis.Methods: Murine bone marrow-derived macrophages or human monocytes were treated using JAK1 and JAK3 selective inhibitors (JAK1i; JAK3i) and tofacitinib and were evaluated by transcriptional, functional, and metabolic analyses. In vivo, oral administration of JAK1i and tofacitinib (10 or 30 mg/kg) was tested in both acute and acute rescue dextran sodium sulfate (DSS) colitis.Results: Both tofacitinib and JAK1i but not JAK3i effectively inhibited STAT1 phosphorylation and interferon gamma-induced transcripts in M1 polarized macrophages. Strikingly, transcriptional profiling suggested a switch from M1 to M2 type macrophages, which was supported by increased protein expression of M2-associated markers. In addition, both inhibitors enhanced oxidative phosphorylation rates. In vivo, JAK1i and tofacitinib did not protect mice from acute DSS-induced colitis but ameliorated recovery from weight loss and disease activity during acute rescue DSS-induced colitis at the highest dose.Conclusion: JAK1i and tofacitinib but not JAK3i induce phenotypical and functional characteristics of anti-inflammatory macrophages, suggesting JAK1 as the main effector pathway for tofacitinib in these cells. In vivo, JAK1i and tofacitinib modestly affect acute rescue DSS-induced colitis.