Role of IL-1 Beta in the Development of Human TH17 Cells: Lesson from NLPR3 Mutated Patients
Role of IL-1 Beta in the Development of Human TH17 Cells: Lesson from NLPR3 Mutated Patients
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DOI：
10.1371/journal.pone.0020014
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发表时间：
2011-05-26
期刊：
影响因子：
3.7
通讯作者：
Gattorno, Marco
中科院分区：
文献类型：
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作者：
Lasiglie, Denise;Traggiai, Elisabetta;Gattorno, Marco
背景：辅助 T 17 细胞 (T-H-17) 代表对宿主防御和自身免疫至关重要的效应 T 细胞谱系。在小鼠和人类中，IL-1β 已被证明是 T-H-17 细胞的关键细胞因子。冷热蛋白相关周期性综合征 (CAPS) 是一组与编码炎性小体成分冷热蛋白的 NLRP3 基因突变相关的炎症性疾病。在这项工作中，我们询问这些患者特有的突变继发的 IL-1 β 分泌失调是否会影响 IL-23/IL-17 轴。 方法/主要发现：对总共 11 名 CAPS、26 名全身性幼年特发性关节炎 (SoJIA) 患者和 20 名健康对照进行了分析。通过ELISA测定评估IL-17和IL-6血清的血清水平。在葡萄球菌肠毒素 B (SEB) 刺激后对 T(H)17 细胞的频率进行定量。通过 ELISA 测定对单核细胞衍生的树突状细胞 (MoDC) 分泌的 IL-1β、IL-23 和 IL-6 进行定量。还对 IL-1 β 阻断治疗前后总共 8 名 CAPS 和 11 名 SoJIA 患者进行了分析。与对照受试者相比，未经治疗的 CAPS 患者表现出 IL-17 血清水平显着升高，并且 T(H)17 出现频率更高。相反，SoJIA 患者的 T(H)17 频率与正常供体相似，但与 CAPS 患者或健康供体相比，血清 IL-6 水平显着升高。值得注意的是，体内 IL-1 β 阻断后，CAPS 患者中观察到 IL-17 血清水平和 T(H)17 频率降低。同样，CAPS 患者的 MoDC 在 TLR 刺激后表现出 IL-1 β 和 IL-23 分泌增强，而抗 IL-1 治疗后分泌减少。 结论/意义：这些发现进一步支持了 IL-1 β 在人类炎症条件下 T(H)17 分化中的核心作用。
Background: T helper 17 cells (T-H-17) represent a lineage of effector T cells critical in host defence and autoimmunity. In both mouse and human IL-1 beta has been indicated as a key cytokine for the commitment to T-H-17 cells. Cryopyrin-associated periodic syndromes (CAPS) are a group of inflammatory diseases associated with mutations of the NLRP3 gene encoding the inflammasome component cryopyrin. In this work we asked whether the deregulated secretion of IL-1 beta secondary to mutations characterizing these patients could affect the IL-23/IL-17 axis.Methodology/Principal Findings: A total of 11 CAPS, 26 systemic onset juvenile idiopathic arthritis (SoJIA) patients and 20 healthy controls were analyzed. Serum levels of IL-17 and IL-6 serum were assessed by ELISA assay. Frequency of T(H)17 cells was quantified upon staphylococcus enterotoxin B (SEB) stimulation. Secretion of IL-1 beta, IL-23 and IL-6 by monocyte derived dendritic cells (MoDCs), were quantified by ELISA assay. A total of 8 CAPS and 11 SoJIA patients were also analysed before and after treatment with IL-1 beta blockade. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of T(H)17 compared to control subjects. On the contrary, SoJIA patients displayed a frequency of T(H)17 similar to normal donors, but were found to have significantly increased serum level of IL-6 when compared to CAPS patients or healthy donors. Remarkably, decreased IL-17 serum levels and T(H)17 frequency were observed in CAPS patients following in vivo IL-1 beta blockade. On the same line, MoDCs from CAPS patients exhibited enhanced secretion of IL-1 beta and IL-23 upon TLRs stimulation, with a reduction after anti-IL-1 treatment.Conclusion/Significance: These findings further support the central role of IL-1 beta in the differentiation of T(H)17 in human inflammatory conditions.