吸烟通过IRF4信号通路途径影响类风湿关节炎的发病

Smoking affects the development of rheumatoid arthritis through the IRF4 signaling pathway

目的比较吸烟与非吸烟类风湿关节炎(rheumatoid arthritis,RA)患者及健康对照(healthy control,HC)外周血单个核细胞(peripheral blood mononuclear cell,PBMC)中干扰素调节因子4(interferon regulatory factor 4,IRF4)、Rho相关蛋白激酶2(Rho-associated protein kinase 2,ROCK2)mRNA的表达水平,探讨吸烟是否通过IRF4信号通路途径影响RA的发病。方法实时荧光定量聚合酶反应(real-time fluorescence quantitative PCR,RT-qPCR)检测PBMC中芳香烃受体(aryl hydrocarbon receptor,AHR)、细胞色素P4501A1(cytochrome P4501A1,CYP1A1)及ROCK2、IRF4 mRNA的表达水平,分析ROCK2、IRF4 mRNA与AHR、CYP1A1 mRNA的表达水平之间相关性,以及各mRNA表达水平与RA患者红细胞沉降率(erythrocyte sedimentation rate,ESR)、C反应蛋白(C-reactive protein,CRP)、抗环瓜氨酸多肽抗体(anti-cyclic citrulline peptide antibody,A-CCP)、类风湿因子(rheumatoid factor,RF)、RA患者28个关节疾病活动评分(disease activity score in 28 joints,DAS28)等临床指标的相关性。结果ROCK2、IRF4 mRNA表达水平在RA病例组中高于HC组,差异均有统计学意义(均有P<0.05);IRF4 mRNA表达水平在RA吸烟组中高于RA非吸烟组,差异有统计学意义(P=0.011);HC吸烟组PBMC中IRF4 mRNA表达水平高于HC非吸烟者,差异有统计学意义(P=0.004)。RA吸烟组中CYP1A1 mRNA与ROCK2及IRF4 mRNA表达水平均呈正相关,同时ROCK2、IRF4 mRNA表达水平与ESR、A-CCP、RF、关节肿胀数(swollen joint count,SJC)均呈正相关。结论RA患者PBMC中ROCK2、IRF4 mRNA表达水平增高,提示这两者可能参与RA的发病;吸烟可能通过活化AHR导致IRF4高表达进而参与RA的发病。

Objective To compare the expression levels of interferon regulatory factor 4(IRF4)and Rho-associated protein kinase 2(ROCK2)mRNA in peripheral blood mononuclear cell(PBMC)of smoking and non-smoking rheumatoid arthritis(RA)patients and healthy control(HC)subjects,and to investigate whether smoking is involved in RA pathogenesis through the IRF4 signaling pathway.Methods Real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of aryl hydrocarbon receptor(AHR),cytochrome P4501 A1(CYP1 A1)and ROCK2,IRF4 mRNA in PBMC,and to analyze the correlation between ROCK2,IRF4 mRNA and AHR,CYP1 A1 mRNA expression levels,as well as the correlation between the expression levels of each mRNA and clinical indicators such as erythrocyte sedimentation rate(ESR),C-reactive protein(CRP),anti-cyclic citrulline peptide antibody(A-CCP),rheumatoid factor(RF)and disease activity score in 28 joints scores in RA patients.Results ROCK2 and IRF4 mRNA expressions were higher in RA group than in HC group,and the differences were statistically significant(all P<0.05);IRF4 mRNA expression levels was higher in RA smoking group than in RA non-smoking group,and the difference was statistically significant(P=0.011);IRF4 mRNA expression levels in PBMC of healthy smokers was higher than that of healthy non-smokers,and the difference was statistically significant(P=0.004).CYP1 A1 mRNA was positively correlated with ROCK2 and IRF4 mRNA expression levels in the RA smoking group,while ROCK2 and IRF4 mRNA expression levels were positively correlated with ESR,A-CCP,RF and swollen joint count.Conclusions ROCK2 and IRF4 mRNA expression levels was increased in PBMC of RA patients,suggesting that both may be involved in the pathogenesis of RA.Smoking may be involved in the pathogenesis of RA by activating AHR leading to high IRF4 expression.