Jak-STAT 信号传导调节炎症 NF-kB 靶基因激活,The Journal of Immunology

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Jak-STAT 信号传导调节炎症 NF-kB 靶基因激活
The Journal of Immunology ( IF 3.6 ) Pub Date : 2023-08-10 , DOI: 10.4049/jimmunol.210.supp.162.01
Bikash Mishra ₁ , Lionel Ivashkiv ₂

Affiliation

摘要巨噬细胞是关键的先天免疫细胞，对宿主防御很重要，但 IFN-γ 对其的异常激活与类风湿性关节炎 (RA) 等慢性炎症性疾病的发病机制有关。IFN-γ 通过蛋白酪氨酸激酶 JAK1/2 发出信号，激活转录因子 STAT1 并驱动干扰素刺激基因 (ISG) 的表达。当受到 Toll 样受体 4 (TLR4) 配体 (LPS) 攻击时，IFN-γ 引发的巨噬细胞诱导经典和非经典 ISG 的快速表达和增强。然而，单独的 IFN-γ 无法引发被认为是促炎 NF-kB 靶基因的非经典 ISG 的表达。基于这一观察，我们假设任何炎症刺激都可以协同激活 IFN-γ 引发的巨噬细胞中的 NF-kB 靶基因。与脂多糖一样，TLR2 配体 (PAM3) 协同诱导 NF-kB 靶基因表达，但炎性细胞因子 TNF-α 在 IFN-γ 引发的巨噬细胞中未能发挥作用。引发的巨噬细胞与 RA 巨噬细胞类似，其中 JAK 信号传导持续进行，STAT1 与炎症 NF-kB 信号传导同时激活。我们的模型表明，靶向抑制 JAK1/2 可能是抑制这些巨噬细胞产生炎症细胞因子的潜在策略。为了解决这个问题，我们使用 FDA 批准的 JAK1/2 抑制剂治疗 RA。JAK 抑制有效抑制了 IFN-γ 诱导基因子集的表达，而 LPS 诱导基因仍然部分抵抗抑制。这表明 IFN-γ 引发会诱导长期表观遗传记忆，即使在抑制 IFN-γ 信号传导后，这种记忆仍然持续存在。

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Regulation of Inflammatory NF-kB Target Gene Activation by Jak-STAT Signaling

Abstract Macrophages are key innate immune cells that are important for host defense but their aberrant activation by IFN-γ has been implicated in the pathogenesis of chronic inflammatory diseases such as rheumatoid arthritis (RA). IFN-γ, signals through protein tyrosine kinases JAK1/2 to activate transcription factor STAT1 and drive the expression of interferon-stimulated genes (ISGs). IFN-γ primed macrophage induced rapid and enhanced expression of both canonical and non-canonical ISGs when challenged with toll-like receptor 4 (TLR4) ligand (LPS). However, IFN-γ alone was not able to elicit the expression of the noncanonical ISGs that are considered proinflammatory NF-kB target genes. Based on this observation, we hypothesized that any inflammatory stimuli can synergistically activate NF-kB target genes in IFN-γ primed macrophages. Like LPS, TLR2 ligand (PAM3) synergistically induced NF-kB target genes expression but inflammatory cytokine TNF-α failed to do so in IFN-γ primed macrophages. The primed macrophage is similar to RA macrophage where JAK signaling is ongoing and STAT1 is activated in tandem with inflammatory NF-kB signaling. Our model suggests that targeted inhibition of JAK1/2 could be a potential strategy to inhibit the production of inflammatory cytokines by these macrophages. To address this, we used an FDA-approved JAK1/2 inhibitor for RA. JAK inhibition effectively suppressed the expression of a subset of IFN-γ-induced genes, whereas LPS induced genes remained partially resistant to inhibition. This suggests that IFN-γ priming induces long term epigenetic memory which persist even after inhibition of IFN-γ signaling.

更新日期：2023-08-10

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