Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland.
Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK.
Nat Commun. 2022 Sep 13;13(1):5346. doi: 10.1038/s41467-022-32927-4.
Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1β serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1β overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1β in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1β in JAK2-V617F mutant mice by anti-IL-1β antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1β with anti-IL-1β antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.
白细胞介素-1β（IL-1β）是炎症的主要调节因子。IL-1β 的活性增加与各种病理状况有关，包括骨髓增生性肿瘤（MPN）。在这里，我们表明 MPN 患者外周血中 IL-1β 血清水平和造血祖细胞和干细胞上 IL-1 受体的表达与 JAK2-V617F 突变等位基因分数相关。我们表明，MPN 小鼠模型中 IL-1β 过度产生的来源是表达 JAK2-V617F 的造血细胞。在 JAK2-V617F 小鼠的造血细胞中敲除 IL-1β 可减少炎性细胞因子，防止巢蛋白阳性龛细胞受损，并减少巨核细胞生成，从而减少骨髓纤维化和骨质硬化。抗 IL-1β 抗体抑制 JAK2-V617F 突变小鼠中的 IL-1β 也可减少骨髓纤维化和骨质硬化，并与鲁索利替尼具有相加作用。这些结果表明，单独使用抗 IL-1β 抗体或与鲁索利替尼联合抑制 IL-1β 可能对骨髓纤维化患者的临床病程有有益影响。
