Ashino Takashi, Arima Yoshiko, Shioda Seiji, Iwakura Yoichiro, Numazawa Satoshi, Yoshida Takemi
Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Tokyo, Japan.
Eur J Pharmacol. 2007 Mar 8;558(1-3):199-207. doi: 10.1016/j.ejphar.2006.11.072. Epub 2006 Dec 12.
Rheumatoid arthritis is characterized by chronic inflammation of the synovial tissue. We examined the effect of interleukin (IL)-6 neutralization on the expression of cytochrome P450 or metallothionein-1/2 (metallothionein) during chronic phase inflammatory disease using rheumatoid arthritis model mice, human T-cell leukemia virus type I (HTLV-I) transgenic mice. Serum IL-6 concentrations of arthritis-developed HTLV-I transgenic mice were 129.9+/-26.1 pg/ml. Moreover, signal transducer and activator of transcription (STAT) 1/3 phosphorylations was observed in arthritic HTLV-I transgenic mouse livers. CYP3A11 mRNA was more strongly reduced by the development of arthritis in HTLV-I transgenic mouse livers as compared with CYP2C29 or CYP2E1 mRNAs. CYP3A protein and testosterone 6beta-hydroxylation activity also changed in a similar manner to the corresponding CYP3A11 mRNA level. On the other hand, metallothionein mRNA was significantly induced as compared with that of wild-type or non-arthritic mice. CYP3A suppression and metallothionein mRNA overexpression activity seen in the developed arthritic mice returned to the gene conditions of the non-arthritic HTLV-I transgenic mice by IL-6 antibody at 48 h after treatment. The present study has revealed that CYP3A11 and metallothionein expressions are affected by the release of IL-6 by arthritis and its systemic circulation, and neutralization of IL-6 recovered from the down-regulation of CYP3A11 mRNA and the induction of metallothionein mRNA in arthritic HTLV-I transgenic mice.
类风湿性关节炎的特征是滑膜组织的慢性炎症。我们使用类风湿性关节炎模型小鼠、I型人类T细胞白血病病毒（HTLV-I）转基因小鼠，研究了白细胞介素（IL）-6中和对慢性炎症性疾病期间细胞色素P450或金属硫蛋白-1/2（金属硫蛋白）表达的影响。发生关节炎的HTLV-I转基因小鼠的血清IL-6浓度为129.9±26.1 pg/ml。此外，在患关节炎的HTLV-I转基因小鼠肝脏中观察到信号转导和转录激活因子（STAT）1/3磷酸化。与CYP2C29或CYP2E1 mRNA相比，HTLV-I转基因小鼠肝脏中关节炎的发展使CYP3A11 mRNA的减少更为明显。CYP3A蛋白和睾酮6β-羟化活性也以与相应CYP3A11 mRNA水平相似的方式发生变化。另一方面，与野生型或未患关节炎的小鼠相比，金属硫蛋白mRNA被显著诱导。在患关节炎的小鼠中观察到的CYP3A抑制和金属硫蛋白mRNA过表达活性，在治疗后48小时通过IL-6抗体恢复到未患关节炎的HTLV-I转基因小鼠的基因状态。本研究表明，CYP3A11和金属硫蛋白的表达受关节炎释放的IL-6及其全身循环的影响，IL-6的中和可恢复患关节炎的HTLV-I转基因小鼠中CYP3A11 mRNA下调和金属硫蛋白mRNA诱导的情况。
