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RAC1 expression and role in IL-1β production and oxidative stress generation in familial Mediterranean fever (FMF) patients.
European Cytokine Network ( IF 2.2 ) Pub Date : 2019-04-30 , DOI: 10.1684/ecn.2018.0416
José-Noel Ibrahim 1 , Rania Jounblat 2 , Nadine Jalkh 3 , Joelle Abou Ghoch 3 , Cynthia Al Hageh 2 , Eliane Chouery 3 , André Mégarbané 4 , Jean-Claude Lecron 5 , Myrna Medlej-Hashim 2
Affiliation  

Objectives

Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder. The caspase-1-dependent cytokine, IL-1β, plays an important role in FMF pathogenesis, and RAC1 protein has been recently involved in IL-1β secretion. This study aims to investigate RAC1 expression and role in IL-1β and caspase-1 production and oxidative stress generation in FMF.

Materials and methods

The study included 25 FMF patients (nine during attack and remission, and 16 during remission only), and 25 controls. RAC1 expression levels were analyzed by real-time PCR. Ex vivo production of caspase-1, IL-1β, IL-6 and markers of oxidative stress (malondialdehyde, catalase, and glutathione system) were evaluated respectively in supernatants of patients’ and controls’ PBMC and PMN cultures, in the presence and absence of RAC1 inhibitor.

Results

RAC1 gene expression and IL-1β levels were increased in patients in crises compared to those in remission or controls. RAC1 expression levels were correlated with MEFV genotypes, patients carrying the M694V/M694V genotype having a two-fold increase in the expression levels compared to those carrying other genotypes. Caspase-1 levels were higher in LPS-induced PBMC of patients in remission than controls. Spontaneous and LPS-induced IL-1β production were comparable in patients in remission and controls, whereas LPS-induced IL-6 production was enhanced in patients, compared to controls. RAC1 inhibition resulted in a decrease in caspase-1 and IL-1β, but not IL-6, levels. Malondialdehyde levels produced by LPS-stimulated PMNs were increased in patients in remission compared to those in controls, but decreased following RAC1 inhibition. Catalase and GSH activities were reduced in unstimulated PMN culture supernatants of patients in remission compared to controls and were increased in the presence of RAC1 inhibitor.

Conclusion

These results show the involvement of RAC1 in the inflammatory process of FMF by enhancing IL-1β production, through caspase-1 activation, and generating oxidative stress, even during asymptomatic periods.


中文翻译:

RAC1在家族性地中海热(FMF)患者中的表达及其在IL-1β产生和氧化应激产生中的作用。

目标

家族性地中海热(FMF)是一种隐性遗传的自体炎症。caspase-1依赖性细胞因子IL-1β在FMF发病机理中起重要作用,而RAC1蛋白最近也参与了IL-1β的分泌。本研究旨在研究RAC1在FMF中的表达及其在IL-1β和caspase-1产生以及氧化应激产生中的作用。

材料和方法

这项研究包括25名FMF患者(其中9名在发作和缓解期间,16名在缓解期间)和25名对照。通过实时PCR分析RAC1表达水平。体外生产胱天蛋白酶-1的,IL-1β,IL-6和氧化应激(丙二醛,过氧化氢酶和谷胱甘肽系统)的标记分别在病人上清液和控制PBMC和PMN培养物进行评估,在存在和不存在RAC1抑制剂。

结果

与缓解或对照组相比,处于危机中的患者的RAC1基因表达和IL-1β水平升高。RAC1表达水平与MEFV相关基因型,携带M694V / M694V基因型的患者的表达水平比携带其他基因型的患者高两倍。在缓解的患者中,LPS诱导的PBMC中Caspase-1水平高于对照组。与对照相比,缓解和对照患者的自发性和LPS诱导的IL-1β产生相当,而患者中LPS诱导的IL-6产生增加。RAC1抑制导致caspase-1和IL-1β降低,但IL-6降低。与对照组相比,LPS刺激的PMN产生的丙二醛水平在缓解患者中升高,但在RAC1抑制后降低。与对照组相比,缓解期未刺激患者的PMN培养上清液中的过氧化氢酶和GSH活性降低,而在RAC1抑制剂存在下则增加。

结论

这些结果表明,即使在无症状时期,RAC1也会通过增强caspase-1的活化来增强IL-1β的产生并产生氧化应激,从而参与FMF的炎症过程。
更新日期:2019-04-30
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