LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy
LIF/JAK2/STAT1 Signaling Enhances Production of Galactose-Deficient IgA1 by IgA1-Producing Cell Lines Derived From Tonsils of Patients With IgA Nephropathy
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DOI：
10.1016/j.ekir.2023.11.003
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发表时间：
2024-02-02
影响因子：
6
通讯作者：
Suzuki，Yusuke
中科院分区：
文献类型：
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作者：
Yamada，Koshi;Huang，Zhi-Qiang;Suzuki，Yusuke
半乳糖缺陷型IgA 1（Gd-IgA 1）在伊加肾病（IgAN）的发病机制中起重要作用。扁桃体切除术对一些IgAN患者是有益的，可能是由于去除了扁桃体中产生Gd-IgA 1的精氨酸激活细胞。为了验证这一假设，我们使用来自IgAN或阻塞性睡眠呼吸暂停（OSA）患者扁桃体的产生IgA 1的永生化细胞系，并评估白血病抑制因子（LIF）或制瘤素M（OSM）对Gd-IgA 1产生的影响。并验证通过使用小干扰RNA（siRNA）敲低和小分子inhibitors. ResultsIgAN衍生的细胞产生更多的Gd-IgA 1比从OSA患者的细胞，并表现出升高的Gd-IgA 1生产响应LIF，但不是OSM。这种效应与STAT 1磷酸化失调有关，这一点通过STAT 1 siRNA敲低证实。JAK 2抑制剂AZD 1480对LIF诱导的Gd-IgA 1的过度产生具有剂量依赖性抑制作用。出乎意料的是，高浓度的AZD 1480（但仅在LIF存在的情况下）使IgAN患者来源的细胞中Gd-IgA 1的产生减少到OSA患者的对照细胞中。基于模型LIF-LIFR-gp 130-JAK 2受体复合物，我们假设LIF结合LIFR可能会隔离gp 130和/或JAK 2从其他途径，并结合JAK 2抑制，使aberrantO-糖基化途径的全面封锁IgAN.ConclusionIn总结，IgAN细胞表现出LIF介导的Gd-IgA 1过度生产由于异常信号。JAK 2抑制剂可以对抗LIF诱导的这些效应并阻断IgAN中Gd-IgA 1的合成。
IntroductionGalactose-deficient IgA1 (Gd-IgA1) plays a key role in the pathogenesis of IgA nephropathy (IgAN). Tonsillectomy has been beneficial to some patients with IgAN, possibly due to the removal of tonsillar cytokine-activated cells producing Gd-IgA1. To test this hypothesis, we used immortalized IgA1-producing cell lines derived from tonsils of patients with IgAN or obstructive sleep apnea (OSA) and assessed the effect of leukemia inhibitory factor (LIF) or oncostatin M (OSM) on Gd-IgA1 production.MethodsGd-IgA1 production was measured by lectin enzyme-linked immunosorbent assay; JAK-STAT signaling in cultured cells was assessed by immunoblotting of cell lysates; and validated by using small interfering RNA (siRNA) knock-down and small-molecule inhibitors.ResultsIgAN-derived cells produced more Gd-IgA1 than the cells from patients with OSA, and exhibited elevated Gd-IgA1 production in response to LIF, but not OSM. This effect was associated with dysregulated STAT1 phosphorylation, as confirmed by STAT1 siRNA knock-down. JAK2 inhibitor, AZD1480 exhibited a dose-dependent inhibition of the LIF-induced Gd-IgA1 overproduction. Unexpectedly, high concentrations of AZD1480, but only in the presence of LIF, reduced Gd-IgA1 production in the cells derived from patients with IgAN to that of the control cells from patients with OSA. Based on modeling LIF-LIFR-gp130-JAK2 receptor complex, we postulate that LIF binding to LIFR may sequester gp130 and/or JAK2 from other pathways; and when combined with JAK2 inhibition, enables full blockade of the aberrantO-glycosylation pathways in IgAN.ConclusionIn summary, IgAN cells exhibit LIF-mediated overproduction of Gd-IgA1 due to abnormal signaling. JAK2 inhibitors can counter these LIF-induced effects and block Gd-IgA1 synthesis in IgAN.