内质网应激蛋白ARMET对关节炎滑膜细胞过度增殖的负性调节作用

沈玉先

摘 要：类风湿关节炎的滑膜细胞能抵抗内质网（ER）应激诱导的凋亡而获得“永生性”。ARMET基因是该课题组从3万个基因中筛选出的对ER应激最敏感的基因，ER应激上调其表达和分泌，但它与炎症的关系未见报道。研究发现：在甲基化牛血清白蛋白诱导的兔关节炎及大鼠佐剂性关节炎模型上，关节局部炎症能诱导ER应激，上调ARMET表达，并且滑膜组织中表达ARMET的细胞类型主要为成纤维样滑膜细胞；关节炎症能诱导ARMET分泌，在炎症不同时期，外周血中ARMET水平明显升高，与急性期反应蛋白CRP变化呈正相关；关节炎滑膜组织中ARMET水平与关节炎症的发展呈负相关。用ARMET siRNA抑制内源性ARMET表达后，细胞增殖能力增强，炎症因子IL-1β21644；TNF-α34920；达和分泌明显增加；而重组人ARMET蛋白能剂量依赖性的抑制炎症滑膜细胞的增殖，降低IL-1β21644；TNF-α30340；表达和分泌。此外，ER应激诱导剂tunicamycin能诱导滑膜细胞中ARMET的核转移。上述结果提示，关节局部炎症可诱导ER应激并上调ARMET表达，ARMET的诱导表达对炎性滑膜细胞的过度激活有抑制作用。

关键词：ARMET 内质网应激 滑膜细胞 佐剂性关节炎

Abstract： Synovial fibroblasts from arthritis mice were resistant to ER-stress-induced apoptosis and gain "eternal life". Armet （Arginine-Rich， Mutated in Early stage Tumors） gene is a commonly upregulated genes under various forms of ER stress in different cell types using microarray analysis， but relationship between ARMET and inflammation has not explored. In our study，Methylated bovine serum albumin （mBSA） and Freund's complete adjuvant （FCA） were employed to establish antigen-induced rabbit and rat arthritis models.The expression of ARMET was remarkably up-regulated in inflammatory synovial tissue， compared to normal controls. More interestingly， ARMET expression only was induced in a-SMA-positive fibroblasts， but not CD68-positive microphages.We also observed the expressions of ER stress inducible proteins and ARMET in synovial tissue were dynamic during different periods of inflammation：BiP was increased significantly early in primary inflammation response （d2～d7）， then maintained at a high level until d28， then decreased slightly； ARMET was upregulated at the early stage of primary inflammation response and then decreased slightly on d14. CHOP expression increased slowly during inflammation development. Above results suggest that ARMET is most sensitive to the inflammation stimulus than BiP and CHOP. The levels of ARMET in peripheral blood serum of AA rats increased on d2 and up-regulated significantly on d14， while serum CRP also exhibited a similar trend of expression. Correlation analysis revealed that arthritissymptoms， serum IL-1βTNF-αevels were negatively correlated with level of ARMET during second inflammation phase.Inhibition of endogenous ARMET expression can increased cell proliferation， promoted IL-1βnd TNF-αxpression and secretion in AA rats-derived synoviocytes. Similarly， recombinant ARMET protein can dose-dependently inhibited cell proliferation， and reduced IL -1βnd TNF-αxpression and secretion. Intriguingly，ARMET was found expressed in the nucleus of FLS while αMA was activated greatly， and tunicamycin induced ARMET nuclear translocation in FLS.These results suggested that ARMET up-regulation plays a protective role in controlling inflammation through inhibiting synoviocytes proliferation and inflammatory cytokines production， which may be related to nuclear transcription regulation of ARMET.

Key Words： ARMET；ER stress；Synovicytes；Adjuvant arthritis

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