Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy
Leukemia Inhibitory Factor Signaling Enhances Production of Galactose-Deficient IgA1 in IgA Nephropathy
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DOI：
10.1159/000505748
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发表时间：
2020-05-01
期刊：
影响因子：
3.7
通讯作者：
Novak, Jan
中科院分区：
文献类型：
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作者：
Yamada, Koshi;Huang, Zhi Qiang;Novak, Jan
目的：IgA肾病(IgAN)是一种自身免疫过程，半乳糖缺乏的IgA1(Gd-IgA1)被自身抗体识别为自身抗原，形成致病免疫复合体。越来越多的证据表明，一些蛋白酪氨酸激酶(PTKs)在IgAN中异常激活。此外，对IgAN的全基因组关联研究(GWAS)提供了对疾病病理生物学和遗传学的洞察。染色体22q12上的一个Gwas基因座包含编码白血病抑制因子(LIF)和抑癌素M、白介素6相关细胞因子的基因，这些细胞因子与粘膜免疫和炎症有关。我们之前已经证明，IL-6通过异常的STAT3激活来调节Gd-IgA1的过度生产。在这里，我们发现LIF促进了IgAN患者IgA1分泌细胞中Gd-IgA1的产生，并提供了LIF信号的初步分析。方法：我们利用来自IgAN患者和健康对照组(HC)外周血中的IgA1分泌细胞系，研究了与Gd-IgA1过度产生有关的LIF信号。我们使用了整体PTK活性图谱、免疫印迹、凝集素ELISA法和siRNA敲击法。结果：LIF刺激对IgAN或HC患者的IgA1分泌细胞的总IgA1的产生无明显影响。然而，LIF增加了Gd-IgA1的产生，但仅在IgAN患者的细胞中。LiF刺激使IgAN患者的IgA1分泌细胞中STAT1的磷酸化程度高于HC患者。下调STAT1的siRNA可阻断LIF介导的Gd-IgA1的过度生产。令人意外的是，在IgAN患者的IgA1分泌细胞中，这种STAT1的异常磷酸化不是由JAK介导的，而是涉及到Src家族PTKs(SFKs)的激活。结论：LIF/STAT1信号通路异常可能是导致Gd-IgA1在IgAN中过度产生的另一种途径，为22q12 Gwas基因座的表型提供了可能的解释。LIF/STAT1信号的异常及其相关的SFK可能是IgAN潜在的诊断和/或治疗靶点。
Objectives: IgA nephropathy (IgAN) is thought to involve an autoimmune process wherein galactose-deficient IgA1 (Gd-IgA1), recognized as autoantigen by autoantibodies, forms pathogenic immune complexes. Mounting evidence has implicated abnormal activation of some protein-tyrosine kinases (PTKs) in IgAN. Furthermore, genome-wide association studies (GWAS) of IgAN provided insight into disease pathobiology and genetics. A GWAS locus on chromosome 22q12 contains genes encoding leukemia inhibitory factor (LIF) and oncostatin M, interleukin (IL)-6-related cytokines implicated in mucosal immunity and inflammation. We have previously shown that IL-6 mediates overproduction of Gd-IgA1 through aberrant STAT3 activation. Here, we show that LIF enhanced production of Gd-IgA1 in IgA1-secreting cells of patients with IgAN and provide initial analyses of LIF signaling. Methods: We characterized LIF signaling that is involved in the overproduction of Gd-IgA1, using IgA1-secreting cell lines derived from peripheral blood of patients with IgAN and healthy controls (HC). We used global PTK activity profiling, immunoblotting, lectin ELISA, and siRNA knock-down. Results: LIF stimulation did not significantly affect production of total IgA1 in IgA1-secreting cells from patients with IgAN or HC. However, LIF increased production of Gd-IgA1, but only in the cells from patients with IgAN. LIF stimulation enhanced phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN to a higher degree than in the cells from HC. siRNA knock-down of STAT1 blocked LIF-mediated overproduction of Gd-IgA1. Unexpectedly, this abnormal phosphorylation of STAT1 in IgA1-secreting cells from patients with IgAN was not mediated by JAK, but rather involved activation of Src-family PTKs (SFKs). Conclusion: Abnormal LIF/STAT1 signaling represents another pathway potentially leading to overproduction of Gd-IgA1 in IgAN, providing possible explanation for the phenotype associated with chromosome 22q12 GWAS locus. Abnormal LIF/STAT1 signaling and the associated SFKs may represent potential diagnostic and/or therapeutic targets in IgAN.