摘要
目的 通过观察系统性红斑狼疮（SLE）患者外周血单个核细胞（PBMCs）中糖皮质激素（GC）受体（GR）α mRNA、热休克蛋白90 （HSP90） mRNA及血浆中巨噬细胞游走抑制因子（MIF）蛋白表达,探讨其与GC抵抗的关系.方法 分离2009年10月至2014年12月大连医科大学附属第一医院106例SLE患者和38例健康对照者的PBMCs,采用实时荧光定量反转录-聚合酶链反应法检测受试者PBMCs中GRα mRNA、HSP90 mRNA表达,酶联免疫吸附试验检测血浆中MIF蛋白表达,并进行Spearman相关分析,多因素logistic逐步回归分析GC抵抗的危险因素.结果 GC抵抗者GRαmRNA、HSP90 mRNA表达显著低于GC敏感者[10.18 （3.12,17.20）比16.83（12.01,24.18）,P=0.001;18.46（14.77,26.45）比25.84（17.97,35.90）,P=0.005],MIF蛋白表达高于GC敏感者[（23.21±7.98） μg/L比（18.34 ±6.29） μg/L;P=0.013].高MIF蛋白表达者HSP90 mRNA表达、HSP90/GRα低于低MIF蛋白表达者[23.67（13.84,28.32）比26.64（23.61,47.16）,P=0.001;1.51（1.02,1.97）比1.64（1.49,4.75）,P=0.008].CG抵抗者SLE疾病活动指数高于GC敏感者（12.23±2.86比9.63±3.48;P=0.003）.MIF蛋白表达与HSP90 mRNA表达、HSP90/GRα呈负相关（r=-0.275,P=0.004;r=-0.341,P＜0.001）.多因素logistic逐步回归显示,SLE疾病活动指数为SLE患者出现GC抵抗的危险因素（OR=17.481,95％ CI1.747 ～ 174.903,P=0.015）.结论 SLE患者GRα mRNA、HSP90 mRNA低表达及MIF蛋白高表达与GC抵抗密切相关,MIF蛋白高表达可能通过下调HSP90 mRNA表达,影响HSP90/GRα比例,削弱GR功能,诱发GC抵抗.高疾病活动度为GC抵抗的危险因素,可能为临床判断GC疗效提供重要依据.
Objective To investigate the mRNA level of glucocorticoid receptor α （GRα） and heat shock protein 90 （HSP90） in peripheral blood mononuclear cells （PBMCs） and the plasma protein level of macrophage migration inhibitory factor （MIF） in patients with systemic lupus erythematosus （SLE） and to analyze their association with glucocorticoid （GC） resistance.Methods One hundred and six patients with SLE and thirty-eight healthy controls were enrolled in this study.Transcription levels of GRα and HSP90 were determined by real-time polymerase chain reaction.Enzyme-linked immunosorbent assay was used to detect the protein level of plasma MIF.The association between these parameters and GC resistance was analyzed by Spearman correlation analysis.The multivariate logistic regression model was used to analyze the risk factors for GC resistance.Results The mRNA level of GRα and HSP90 in GC resistance group was significantly lower than that in GC sensitive group [10.18（3.12,17.20） vs 16.83（12.01,24.18）, P =0.001;18.46（14.77,26.45） vs 25.84 （17.97,35.90）, P =0.005].MIF protein level in GC resistance group was significantly higher than that in GC sensitive group [（23.21 ±7.98） μg/L vs （18.34 ±6.29）μg/L;P =0.013].The mRNA level of HSP90 in the high MIF group was significantly lower than that in the low MIF group [23.67 （13.84,28.32） vs 26.64 （23.61,47.16）;P =0.001], as well as HSP90/GRαratio（P =0.008）.Additionally, the plasma protein level of MIF was negatively correlated with HSP90 （r =-0.275, P =0.004） and HSP90/GRα ratio（r =-0.341, P 〈 0.001）.SLE activity index score in GC resistance group was significantly higher than that in GC sensitive group [（12.23 ±2.86） μg./L vs （9.63 ± 3.48） μg/L;P =0.003].Logistic regression model indicated that disease activity was an independent risk factor for GC resistance （OR =17.481, 95% CI 1.747-174.903, P =0.015）.Conclusions Our preliminary findings suggest that low mRNA level of GRα and HSP90 and high protein level of MIF are associated with GC resistance.Elevated MIF level in SLE patients may play an important role in the development of GC resistance through down-regulating HSP90 and destabilizing the balance of HSP90/ Grα.Disease activity is the risk factor for GC resistance, which might be the viable evidence of therapy response.
出处
《中华内科杂志》
CAS
CSCD
北大核心
2015年第11期922-926,共5页
Chinese Journal of Internal Medicine
基金
国家自然科学基金（81370604）
辽宁省社会发展攻关计划（2013225002-208）
大连医科大学附属第一医院院青年基金（2014QN002）
