JAK-STAT 通路在诱导炎症性疾病和骨髓增生性肿瘤（MPN）中与多种细胞因子的信号级联中发挥着关键作用。在 JAKs 的异构体中，JAK2 亚型主要负责造血系统细胞的功能，使其成为 MPN 治疗中的一个重要靶标。然而，JAK2 在炎症性疾病中的精确调控作用需要进一步研究和确认。本研究采用了一种源于菘蓝根的 JAK2 选择性抑制剂 ZT55，以检验其对小鼠延迟型超敏反应（DTH）和关节炎中炎症和免疫反应的调控效果。为评估 ZT55 治疗的疗效，我们采用了 DNFB 诱导的 DTH 和胶原诱导的关节炎（CIA）小鼠模型。通过流式细胞术和 EdU 分析，培养T细胞，并对其增殖和活化进行分析。此外，通过流式细胞术和 ELISA 评估树突状细胞的成熟和功能。我们的研究结果表明，ZT55 显著减少了 DNFB 诱导的 DTH 并减轻了 CIA 小鼠的炎症、软骨降解和骨破坏。此外，我们发现ZT55 通过调控 JAK2-STAT3 信号通路来抑制 T 细胞的增殖和活化以及树突状细胞的成熟。这些结果表明，通过调节 JAK2-STAT3 信号通路，选择性靶向 JAK2 亚型具有抗炎和免疫抑制作用，调控适应性和先天性免疫反应。因此，ZT55 对于治疗炎症和自身免疫性疾病具有潜在的药物候选价值。 版权所有 © 2023 Elsevier B.V. 保留所有权利。

The JAK-STAT pathway plays a crucial role in the signaling cascade associated with various cytokines that have been implicated in the pathogenesis of inflammatory diseases and myeloproliferative neoplasms (MPN). Among the isoforms of JAKs, the JAK2 subtype is primarily responsible for the function of hematopoietic system cells, making it a significant target in the treatment of MPN. However, the precise regulatory role of JAK2 in inflammatory diseases requires further investigation and confirmation. The current study employed a selective JAK2 inhibitor, ZT55, derived from Isatis indigotica roots, to examine its regulatory effects on inflammatory and immune responses in delayed-type hypersensitivity (DTH) and arthritis in mice. To evaluate the efficacy of ZT55 treatment, DNFB-induced DTH and collagen-induced arthritis (CIA) mouse models were utilized. T cells were cultured and subsequently analyzed for proliferation and activation using flow cytometry and EdU assay. Additionally, the maturation and function of dendritic cells were assessed through flow cytometry and ELISA. Our findings indicate that ZT55 significantly reduced DNFB-induced DTH and attenuated inflammation, cartilage degradation, and bone destruction in CIA mice. Moreover, ZT55 was found to inhibit the proliferation and activation of T cells and the maturation of dendritic cells by regulating the JAK2-STAT3 signaling pathway. These results suggest that selectively targeting the JAK2 isoform could have anti-inflammatory and immunosuppressive effects by regulating the adaptive and innate immune responses via the JAK2-STAT3 signaling pathway. Therefore, ZT55 has the potential to be a promising pharmaceutical candidate for the treatment of inflammatory and autoimmune diseases.Copyright © 2023 Elsevier B.V. All rights reserved.