Defective Phosphorylation of Interleukin-18 Receptor β Causes Impaired Natural Killer Cell Function in Systemic-Onset Juvenile Idiopathic Arthritis
Defective Phosphorylation of Interleukin-18 Receptor β Causes Impaired Natural Killer Cell Function in Systemic-Onset Juvenile Idiopathic Arthritis
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DOI：
10.1002/art.24750
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发表时间：
2009-09-01
影响因子：
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通讯作者：
Prakken, Berent J.
中科院分区：
文献类型：
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作者：
de Jager, Wilco;Vastert, Sebastiaan J.;Prakken, Berent J.
目的。全身型幼年特发性关节炎（JIA）是一种以关节炎和全身症状为特征的自身免疫性疾病。其发病机制在很大程度上仍不清楚。在免疫学上，它的特征是自然杀伤（NK）细胞功能障碍以及以白细胞介素 - 1（IL - 1）、IL - 6和IL - 18为主的细胞因子特征。由于IL - 18可驱动NK细胞功能，我们研究了这种细胞因子的血浆高水平与这些患者中已记录的NK细胞功能异常之间的关系。
方法。通过体外染色和功能测定，对10名健康对照受试者、15名多关节型JIA患者和15名全身型JIA患者的NK细胞表型和功能进行了表征。通过荧光显微镜观察IL - 18配体结合情况。通过蛋白质印迹法观察几种丝裂原活化蛋白激酶和IL - 18受体β（IL - 18Rβ）的磷酸化情况。
结果。全身型JIA患者血浆中的IL - 18刺激了健康对照者的NK细胞活化并与其同源受体结合。然而，全身型JIA患者的NK细胞在IL - 18刺激后未能上调细胞介导的杀伤分子，如穿孔素和干扰素 - γ。此外，IL - 18处理未诱导NK细胞中受体激活的丝裂原活化蛋白激酶磷酸化。IL - 12对NK细胞的替代激活诱导了NK细胞的细胞毒性。我们观察到在全身型JIA患者中，IL - 18与IL - 12联合使用没有累加效应。IL - 18Rβ的免疫沉淀显示，全身型JIA患者的NK细胞在IL - 18刺激后不能使该受体磷酸化。
结论。全身型JIA中NK细胞功能受损的机制涉及IL - 18Rβ磷酸化缺陷。这一观察结果对理解并最终治疗全身型JIA具有重要意义。
Objective. Systemic-onset juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by arthritis and systemic features. Its pathogenesis is still largely unknown. It is characterized immunologically by natural killer (NK) cell dysfunction and cytokine signatures that predominantly feature interieukin-1 (IL-1), IL-6, and IL-18. Since IL-18 can drive NK cell function, we examined how the high plasma levels of this cytokine are related to the documented NK cell failure in these patients.Methods. The phenotype and function of NK cells from 10 healthy control subjects, 15 patients with polyarticular JIA, and 15 patients with systemic-onset JIA were characterized by staining and functional assays in vitro. IL-18 ligand binding was visualized by fluorescence microscopy. Phosphorylation of several MAP kinases and the IL-18 receptor beta (IL-18R beta) were visualized by Western blotting.Results. IL-18 from the plasma of systemic-onset JIA patients stimulated the activation of NK cells from healthy controls and bound its cognate receptor. However, NK cells from systemic-onset JIA patients failed to up-regulate cell-mediated killing molecules, such as perforin and interferon-gamma, after IL-18 stimulation. Furthermore, treatment with IL-18 did not induce the phosphorylation of receptor-activated MAP kinases in NK cells. Alternate activation of NK cells by IL-12 induced NK cell cytotoxicity. We observed no additive effect of IL-18 in combination with IL-12 in systemic-onset JIA patients. Immunoprecipitation of IL-18R beta showed that NK cells from systemic-onset JIA could not phosphorylate this receptor after IL-18 stimulation.Conclusion. The mechanism of the impaired NK cell function in systemic-onset JIA involves a defect in IL-18R beta phosphorylation. This observation has major implications for the understanding and, ultimately, the treatment of systemic-onset JIA.