Martel-Pelletier J, Mineau F, Tardif G, Fernandes J C, Ranger P, Loose L, Pelletier J P
Department of Medicine, University of Montreal, Canada.
J Rheumatol. 1996 Jan;23(1):24-31.
To investigate the effects of tenidap, a new antirheumatic drug, sodium diclofenac, a non-steroidal antiinflammatory drug, and a disease modifying antirheumatic drug, hydroxychloroquine, on the level and expression of interleukin 1 receptors (IL-1R) on synovial fibroblasts from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, the effect of tenidap on IL-1 stimulated collagenase gene expression was studied.
Binding assays were performed using [125I]-IL-1 beta as radioligand. Flow cytometry was done using a specific antibody against type I IL-1R. Protein synthesis was determined by [3H]-leucine incorporation. Levels of expression were determined by Northern Blot for collagenase and by reverse transcription polymerase chain reaction (RT-PCR) for type I IL-1R.
Tenidap produced for both OA and RA synovial fibroblasts a dose dependent decrease in the number of IL-1 binding sites/cell. A reduction of 41% (2.5 micrograms/ml) to 81% (at therapeutic concentration, 20 micrograms/ml) was noted for OA, while 29% (2.5 micrograms/ml) to 89% (20 micrograms/ml) was found for RA cells. Diclofenac produced no effect on OA cells, and minimal inhibition of RA synovial fibroblasts was observed only at pharmacological concentration (12%, 300 mg/ml). Hydroxychloroquine had effects similar to diclofenac. The decreased number of IL-1 binding sites/cell by tenidap was time dependent and reached 93% inhibition after 48 h. The effect of tenidap appears to be posttranscriptional, judged by the marked reduction of the type I IL-1R protein/cell and the absence of effect on its mRNA level. Tenidap also markedly reduced the IL-1 induced collagenase expression in synovial fibroblasts.
At therapeutic concentrations tenidap is a potent inhibitor of type I IL-1R in OA and RA synovial fibroblasts. The effect of tenidap was considerably more marked than diclofenac or hydroxychloroquine.
研究新型抗风湿药物替硝唑、非甾体抗炎药双氯芬酸钠以及病情缓解抗风湿药羟氯喹对骨关节炎（OA）和类风湿关节炎（RA）患者滑膜成纤维细胞白细胞介素1受体（IL-1R）水平及表达的影响。此外，还研究了替硝唑对IL-1刺激的胶原酶基因表达的作用。
使用[125I]-IL-1β作为放射性配体进行结合试验。使用抗I型IL-1R的特异性抗体进行流式细胞术检测。通过[3H]-亮氨酸掺入法测定蛋白质合成。通过Northern印迹法检测胶原酶的表达水平，通过逆转录聚合酶链反应（RT-PCR）检测I型IL-1R的表达水平。
替硝唑使OA和RA滑膜成纤维细胞的IL-1结合位点/细胞数量呈剂量依赖性减少。OA细胞减少了41%（2.5微克/毫升）至81%（治疗浓度20微克/毫升时），而RA细胞减少了29%（2.5微克/毫升）至89%（20微克/毫升）。双氯芬酸钠对OA细胞无作用，仅在药理浓度（12%，300毫克/毫升）时对RA滑膜成纤维细胞有最小程度的抑制。羟氯喹的作用与双氯芬酸钠相似。替硝唑使IL-1结合位点/细胞数量减少具有时间依赖性，48小时后达到93%的抑制率。从I型IL-1R蛋白/细胞显著减少且对其mRNA水平无影响判断，替硝唑的作用似乎是转录后水平的。替硝唑还显著降低了滑膜成纤维细胞中IL-1诱导的胶原酶表达。
在治疗浓度下，替硝唑是OA和RA滑膜成纤维细胞中I型IL-1R的有效抑制剂。替硝唑的作用比双氯芬酸钠或羟氯喹显著得多。
