英夫利昔单抗治疗对类风湿关节炎患者肿瘤坏死因子α、锌指蛋白36、T细胞胞内抗原1及Hu抗原R基因表达水平的影响

Effects of infliximab therapy on gene expression levels of tumor necrosis factor alpha, tristetraprolin, T cell intracellular antigen 1, and Hu antigen R in patients with rheumatoid arthritis.

作者信息

Sugihara Makoto, Tsutsumi Akito, Suzuki Eiji, Wakamatsu Ei, Suzuki Takeshi, Ogishima Hiroshi, Hayashi Taichi, Chino Yusuke, Ishii Wataru, Mamura Mizuko, Goto Daisuke, Matsumoto Isao, Ito Satoshi, Sumida Takayuki

机构信息

University of Tsukuba, Tsukuba, Ibaraki, Japan.

出版信息

Arthritis Rheum. 2007 Jul;56(7):2160-9. doi: 10.1002/art.22724.

DOI:10.1002/art.22724

PMID:17599736

Abstract

OBJECTIVE

Tristetraprolin (TTP), T cell intracellular antigen 1 (TIA-1), and Hu antigen R (HuR) are adenine/uridine-rich element binding proteins (ABPs) that affect the production of tumor necrosis factor alpha (TNFalpha) by binding to TNF messenger RNA (mRNA). TTP promotes deadenylation, TIA-1 inhibits translation, and HuR stabilizes TNFalpha mRNA. The aims of this study were to understand the posttranscriptional control of TNFalpha production in patients with rheumatoid arthritis (RA), and to identify parameters that may predict the efficacy of anti-TNFalpha therapy.

METHODS

Peripheral blood mononuclear cells from 38 patients with RA were obtained before therapy and 2 weeks and 54 weeks after administration of the first dose of infliximab, and from 20 healthy control subjects. TNFalpha, TTP, TIA-1, and HuR gene expression levels were analyzed by real-time polymerase chain reaction.

RESULTS

At baseline, TTP and HuR gene expression levels, as well as the TTP:TNFalpha, TTP:HuR, and TIA-1:TNFalpha gene expression ratios were lower in patients with RA than in control subjects, while expression of TNFalpha, TIA-1, and TIA-1:HuR was higher in patients with RA. The TTP:HuR expression ratio decreased significantly after administration of infliximab. Positive correlations were observed between TNFalpha and TTP, TNFalpha and TIA-1, TIA-1 and HuR, and TNFalpha and HuR gene expression in both healthy control subjects and patients with RA. At baseline, the TIA-1:HuR ratio tended to be higher in patients who achieved 50% improvement according to the American College of Rheumatology criteria (ACR50) at week 54 than in those who did not achieve at least an ACR20 response.

CONCLUSION

Differences in ABP gene expression may affect TNFalpha gene expression. A higher TIA-1:HuR expression ratio might correlate with the response to infliximab therapy.

摘要

目的

锌指蛋白36（TTP）、T细胞内抗原1（TIA-1）和Hu抗原R（HuR）是富含腺嘌呤/尿嘧啶元件结合蛋白（ABP），它们通过与肿瘤坏死因子α（TNFα）信使核糖核酸（mRNA）结合来影响TNFα的产生。TTP促进去腺苷酸化，TIA-1抑制翻译，而HuR使TNFα mRNA稳定。本研究的目的是了解类风湿关节炎（RA）患者中TNFα产生的转录后调控，并确定可能预测抗TNFα治疗疗效的参数。

方法

在治疗前、首次输注英夫利昔单抗后2周和54周，从38例RA患者以及20名健康对照者获取外周血单个核细胞。通过实时聚合酶链反应分析TNFα、TTP、TIA-1和HuR基因表达水平。

结果

在基线时，RA患者的TTP和HuR基因表达水平以及TTP:TNFα、TTP:HuR和TIA-1:TNFα基因表达比值低于对照者，而RA患者的TNFα、TIA-1以及TIA-1:HuR表达较高。输注英夫利昔单抗后，TTP:HuR表达比值显著降低。在健康对照者和RA患者中，均观察到TNFα与TTP、TNFα与TIA-1、TIA-1与HuR以及TNFα与HuR基因表达之间呈正相关。在基线时，根据美国风湿病学会标准（ACR50）在第54周达到50%改善的患者中，TIA-1:HuR比值往往高于未达到至少ACR20反应的患者。