Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria.
Clin Exp Rheumatol. 2011 Nov-Dec;29(6):963-9. Epub 2011 Dec 22.
OBJECTIVES: Methotrexate (MTX) is a cornerstone in the treatment of rheumatoid arthritis (RA). Among its anti-proliferative activity, the anti-inflammatory mechanisms of MTX seem to play a major role in the treatment of RA. MTX reduces the production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6 and interferon (INF)-γ, while the gene expression of anti-inflammatory Th2 cytokines like IL-4 and IL-10 is increased - altogether resulting in the anti-inflammatory effect. As little is known about the impact of MTX on other cytokines involved in the pathogenesis of RA, the present trial investigated the effect of MTX on IL-12A and IL-18 gene expression by peripheral blood mononuclear cells (PBMCs). For comparison, the effect on IL-6 and tumour necrosis factor (TNF) was analysed. METHODS: Using real-time PCR, mRNA concentrations of pro-inflammatory cytokines were determined in PBMCs from 17 patients before and during MTX therapy. Furthermore, gene expression was correlated with clinical and pharmacokinetic parameters such as methotrexate polyglutamate concentrations (Spearman's correlation coefficient). To eliminate concomitant corticosteroids as confounding factor, a subgroup analysis for methotrexate without corticosteroids was performed in 6 patients. RESULTS: MTX statistically significantly reduced the mRNA expression of IL-12A by PBMCs in rheumatoid arthritis patients (Wilcoxon-test for paired samples, p<0.046). Consistent with other reports, IL-6 was reduced under MTX treatment. Although the combination of MTX and corticosteroids significantly reduced the gene expression of IL-18, this key molecule was unaffected by MTX without corticosteroids. Our results were further supported by a negative correlation of methotrexate polyglutamate concentrations and the mRNA expression of the pro-inflammatory cytokines IL-6 and IL-12A. CONCLUSIONS: We describe a novel effect of MTX reducing the gene expression of IL-12A independently of corticosteroid application in patients. This impact was further enhanced by a reduction of IL-12A-producing lymphocytes and neutrophils under MTX treatment. These results expand the understanding of the mechanism of action of the most widely used drug in RA.
目的：甲氨蝶呤（MTX）是治疗类风湿关节炎（RA）的基石。在其抗增殖活性中，MTX 的抗炎机制似乎在 RA 的治疗中起主要作用。MTX 减少促炎细胞因子的产生，如白细胞介素（IL）-1、IL-2、IL-6 和干扰素（IFN）-γ，同时增加抗炎 Th2 细胞因子如 IL-4 和 IL-10 的基因表达 - 总的来说，这会产生抗炎作用。由于对 MTX 对 RA 发病机制中涉及的其他细胞因子的影响知之甚少，因此本试验研究了 MTX 对外周血单个核细胞（PBMC）中 IL-12A 和 IL-18 基因表达的影响。为了进行比较，还分析了对 IL-6 和肿瘤坏死因子（TNF）的影响。
方法：使用实时 PCR，在 17 例接受 MTX 治疗前后的患者的 PBMC 中测定促炎细胞因子的 mRNA 浓度。此外，基因表达与临床和药代动力学参数（如 MTX 多聚谷氨酸浓度）相关（Spearman 相关系数）。为了消除伴随的皮质类固醇作为混杂因素，在 6 例患者中进行了没有皮质类固醇的 MTX 的亚组分析。
结果：MTX 可统计学显著降低 RA 患者 PBMC 中 IL-12A 的 mRNA 表达（配对样本 Wilcoxon 检验，p<0.046）。与其他报道一致，IL-6 在 MTX 治疗下减少。尽管 MTX 与皮质类固醇联合可显著降低 IL-18 的基因表达，但在没有皮质类固醇的情况下，该关键分子不受 MTX 影响。我们的结果进一步得到了 MTX 多聚谷氨酸浓度与促炎细胞因子 IL-6 和 IL-12A 的 mRNA 表达之间的负相关的支持。
结论：我们描述了 MTX 减少患者中 IL-12A 基因表达的新作用，这一作用在 MTX 治疗下减少产生 IL-12A 的淋巴细胞和中性粒细胞时进一步增强。这些结果扩展了对 RA 中最广泛使用的药物作用机制的理解。
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