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Diacerhein and rhein reduce the ICE-induced IL-1β and IL-18 activation in human osteoarthritic cartilage

软骨 污渍 原位杂交 骨关节炎 免疫组织化学 体外 化学 细胞因子 信使核糖核酸 分子生物学 医学 白细胞介素 药理学 软骨细胞 内科学 病理 生物化学 生物 解剖 基因 替代医学
作者
Florina Moldovan,Jean‐Pierre Pelletier,F C Jolicoeur,J M Cloutier,Johanne Martel‐Pelletier
出处
期刊:Osteoarthritis and Cartilage [Elsevier]
卷期号:8 (3): 186-196 被引量:85
标识
DOI:10.1053/joca.1999.0289
摘要

IL-1beta plays a fundamental role in osteoarthritis (OA) pathophysiology and cartilage destruction. Targeting the activation mechanism of this cytokine appears to be important as a therapeutic approach. As the interleukin-1 converting enzyme (ICE) is the physiologic modulator of the production of active IL-1beta, we investigated the effect of diacerhein and its active metabolite rhein used in the treatment of OA patients, on the enzyme expression and synthesis on human OA cartilage. Further, we looked at the effect of both drugs on the production of the active form of IL-1beta and IL-18.The expression and synthesis of ICE were investigated on human OA cartilage explants using in-situ hybridization and immunohistochemical methods, respectively. The effect of the drugs on ICE OA chondrocytes was also determined by Northern blotting and a specific ELISA assay. Furthermore, the effect of both drugs on the level of active IL-1beta and IL-18 was examined by immunohistochemistry.Data showed that diacerhein and rhein have no true effect on reducing total ICE mRNA by both Northern blotting analysis and in-situ hybridization. A marked and statistically significant decrease was, however, found for protein production. ELISA showed a reduction of 31% (P< 0.04) for diacerhein and 50% (P< 0.02) for rhein. The drugs' immunohistological cell score reduction was similar to data from the ELISA, and a statistical significant reduction of ICE production was found at both superficial and deep zones of the cartilage. IL-1beta and IL-18 were both preferentially produced in chondrocytes of the superficial zone. For each of these cytokines, both drugs demonstrated a statistically significant decrease in this zone. A marked decrease was also noted in the deep zone, but statistical significance was reached only for rhein.These results provide a novel regulatory mechanism by which diacerhein and rhein could exert a down-regulation on IL-1's effect on OA cartilage.
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