Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis
Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis
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DOI：
10.1016/j.intimp.2013.03.020
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发表时间：
2013-05-01
影响因子：
5.6
通讯作者：
Ju, Ji Hyeon
中科院分区：
文献类型：
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作者：
Kang, Kwi Young;Kim, Young Kyun;Ju, Ji Hyeon
简介：本研究旨在确定二甲双胍在胶原抗体诱导的关节炎（CAIA）小鼠模型中是否具有抗炎作用。二甲双胍对Th 17细胞分化的影响也investigated.Methods：CAIA小鼠用100和150 mg/kg i. p.二甲双胍（低和高剂量组，分别）处理。关节炎活动和组织学关节破坏进行了研究。流式细胞术用于（i）测定来自二甲双胍处理和未处理的CAIA小鼠的引流腋窝淋巴结（ALN）中表达ROR γ t的CD 4+百分比，（ii）测定在Th 17分化诱导条件下离体培养3天的脾CD 4 + T细胞中的Th 17百分比，和（iii）当来自DBA/1小鼠的正常脾T细胞与各种二甲双胍一起在Th 17分化诱导条件下培养时，测定ROR γ t + CD 4 + T细胞的百分比。Western blot分析被用来评估二甲双胍处理的脾细胞的细胞内信号转导。结果：二甲双胍减弱了CAIA小鼠的关节炎评分和骨破坏，降低了促炎细胞因子TNF-α和IL-1的血清水平，并减少了ALNs中ROR γ t + CD 4 + T细胞的数量。二甲双胍处理的CAIA小鼠的脾细胞在离体刺激后不易分化为Th 17细胞。在Th 17-分化诱导条件下培养的正常细胞的二甲双胍治疗以剂量依赖性方式降低了ROR γ t表达的CD 4+细胞的数量，并通过AMPK pathway下调了STAT 3磷酸化。结论：二甲双胍对小鼠自身免疫性关节炎具有抗炎作用，这是由于抑制了Th 17细胞分化。美托洛尔可能对类风湿关节炎有潜在的治疗价值。(C)2013爱思唯尔有限公司版权所有。
Introduction: This study was undertaken to determine whether metformin has anti-inflammatory effects in the collagen antibody-induced arthritis (CAIA) murine model. The effect of metformin on Th17 cell differentiation was also investigated.Methods: CAIA mice were treated with 100 and 150 mg/kg i.p. metformin (low- and high-dose groups, respectively). Arthritis activity and histological joint destruction were studied. Flow cytometry was used to (i) determine ROR gamma t-expressing CD4+ percentages in draining axillary lymph nodes (ALNs) from metformin-treated and untreated mice with CAIA, (ii) determine Th17 percentages in splenic CD4+ T cells cultured ex vivo for 3 days in Th17-differentiation-inducing conditions, and (iii) determine the percentages of ROR gamma t + CD4+ T cells when normal splenic T cells from DBA/1 mice were cultured in Th17-differentiation-inducing conditions together with various metformin doses. Western blot analysis was used to assess the intracellular signaling of the metformin-treated splenocytes.Results: Metformin attenuated both arthritis scores and bone destruction in CAIA mice, decreased the serum levels of the pro-inflammatory cytokines, TNF-alpha and IL-1, and reduced the number of ROR gamma t + CD4+ T cells in the ALNs. Splenocytes from metformin-treated CAIA mice differentiated less readily into Th17 cells upon ex vivo stimulation. Metformin treatment of normal cells cultured in Th17-differentiation-inducing conditions decreased the number of ROR gamma t-expressing CD4+ cells in a dose-dependent manner and downregulated STAT3 phosphorylation via the AMPK pathway.Conclusions: Metformin had an anti-inflammatory effect on murine autoimmune arthritis due to the inhibition of Th17 cell differentiation. Metformin may have a possible therapeutic value for treatment of rheumatoid arthritis. (C) 2013 Elsevier B.V. All rights reserved.