Gene Polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation
Gene Polymorphisms in the NALP3 inflammasome are associated with interleukin-1 production and severe inflammation
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DOI：
10.1002/art.23286
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发表时间：
2008-03-01
影响因子：
--
通讯作者：
Sarndahl, Eva
中科院分区：
文献类型：
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作者：
Verma, Deepti;Lerm, Maria;Sarndahl, Eva
Objective. NALP 3、ASC和TUCAN是NALP 3炎性体的组分，其触发半胱天冬酶1介导的白细胞介素-1 β（IL-1 β）释放。编码NALP 3（NLRP 3）的基因中的激活突变最近与家族性周期性发热综合征有关。我们进行这项研究是为了确定关节炎和抗生素耐药性发热患者是否携带编码NALP 3炎性体的基因突变。方法。对来自患者和来自基于群体的DNA收集物（806名受试者）的基因组DNA进行NLRP 3和编码TUCAN（CARD-8）的基因的遗传分析。对于IL-1 β产生和caspase I活性的体外研究，在给予阿那白滞素（一种IL-1受体拮抗剂）后的不同时间点从患者以及5名年龄和性别匹配的健康对照受试者中采集血液。对患者编码NALP 3、ASC和TUCAN的基因的突变分析揭示了NLRP 3（Q705 K）和CARD-8（C10 X）基因的变异。这些单核苷酸多态性（SNPs）的等位基因频率在人群中分别为6.5%和34%。阿那白滞素治疗后，患者样本中caspase I活性升高和IL-1，6水平升高恢复正常。我们的研究结果表明，患者的症状是由于IL-1 β水平升高，因为阿那白滞素治疗有效地消除了症状。复合SNP可以解释观察到的IL-1 β水平增加和炎症症状，但需要进一步研究来揭示功能关系。在一般人群中多态性的患病率（4%的人群携带两种SNP）可能表明常见炎症性疾病的遗传易感性。
Objective. NALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1-mediated interleukin-1 beta (IL-1 beta) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic-resistant fever carried mutations in the genes encoding the NALP3 inflammasome.Methods. Genetic analysis of NLRP3 and the gene encoding TUCAN (CARD-8) was performed on genomic DNA from the patient and from a population-based collection of DNA (806 subjects). For in vitro studies of IL-1 beta production and caspase I activity, blood was obtained from the patient at different time points after administration of anakinra, an IL-1 receptor antagonist, as well as from 5 healthy age- and sex-matched control subjects.Results. Mutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD-8 (C10X) genes. The allele frequencies of these single-nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase I and the high levels of IL-1,6 measured in samples from the patient returned to normal levels after treatment with anakinra.Conclusion. Our results indicate that the patient's symptoms were due to elevated levels of IL-1 beta, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL-1 beta levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.