Luo Xinjing, Zuo Xiaoxia, Zhou Yaou, Zhang Bing, Shi Yongzhong, Liu Meidong, Wang Kangkai, McMillian D Randy, Xiao Xianzhong
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Xiangya Road, Changsha, Hunan 410008, China.
Arthritis Res Ther. 2008;10(2):R41. doi: 10.1186/ar2399. Epub 2008 Apr 14.
It was recently suggested that heat shock protein (HSP)70, an intracellular protein, is a potential mediator of inflammatory disease when it is released into the extracellular compartment. Although elevated HSP70 levels have been identified in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid compared with patients with osteoarthritis and healthy individuals, it remains unclear what role extracellular HSP70 plays in the pathogenesis of RA. This study was conducted to investigate the effects of extracellular HSP70 on the production of RA-associated cytokines in fibroblast-like synoviocytes from patients with RA and to elucidate the mechanisms involved.
IL-6, IL-8 and monocyte chemoattractant protein (MCP)-1 levels in culture supernatants were measured using enzyme-linked immunosorbent assays. Activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated protein kinases (ERKs), c-Jun amino-terminal kinase (JNK) and p38 MAPK, was detected using Western blotting. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) and degradation of the inhibitory protein IkappaBalpha were examined using immunohistochemistry and Western blotting.
Human HSP70 downregulated IL-6, IL-8 and MCP-1 production in RA fibroblast-like synoviocytes induced by tumour necrosis factor (TNF)-alpha in a concentration dependent manner. HSP70 inhibited the activation of ERK, JNK and p38 MAPK in fibroblast-like synoviocytes stimulated by TNF-alpha. Furthermore, HSP70 also significantly inhibited nuclear translocation of nuclear factor-kappaB and degradation of IkappaBalpha induced by TNF-alpha.
Extracellular HSP70 has an anti-inflammatory effect on RA by downregulating production of IL-6, IL-8 and MCP-1 in fibroblast-like synoviocytes, which is mediated through inhibited activation of the MAPKs and NF-kappaB signal pathways.
最近有研究表明，细胞内蛋白质热休克蛋白（HSP）70释放到细胞外区室时，是炎症性疾病的潜在介质。虽然与骨关节炎患者和健康个体相比，类风湿关节炎（RA）滑膜组织和RA滑液中的HSP70水平升高，但细胞外HSP70在RA发病机制中所起的作用仍不清楚。本研究旨在探讨细胞外HSP70对RA患者成纤维样滑膜细胞中RA相关细胞因子产生的影响，并阐明其中涉及的机制。
采用酶联免疫吸附测定法检测培养上清液中白细胞介素（IL）-6、IL-8和单核细胞趋化蛋白（MCP）-1的水平。使用蛋白质免疫印迹法检测丝裂原活化蛋白激酶（MAPK）的激活情况，如细胞外信号调节蛋白激酶（ERK）、c-Jun氨基末端激酶（JNK）和p38 MAPK。采用免疫组织化学和蛋白质免疫印迹法检测核因子κB（NF-κB）的核转位及抑制蛋白IκBα的降解。
人HSP70以浓度依赖性方式下调肿瘤坏死因子（TNF）-α诱导的RA成纤维样滑膜细胞中IL-6、IL-8和MCP-1的产生。HSP70抑制TNF-α刺激的成纤维样滑膜细胞中ERK、JNK和p38 MAPK的激活。此外，HSP70还显著抑制TNF-α诱导的核因子κB的核转位及IκBα的降解。
细胞外HSP70通过下调成纤维样滑膜细胞中IL-6、IL-8和MCP-1的产生，对RA具有抗炎作用，这是通过抑制MAPK和NF-κB信号通路的激活介导的。
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