內質網應激蛋白ARMET對關節炎滑膜細胞過度增殖的負性調節作用

沈玉先

摘 要：類風濕關節炎的滑膜細胞能抵抗內質網（ER）應激誘導的凋亡而獲得“永生性”。ARMET基因是該課題組從3萬個基因中篩選出的對ER應激最敏感的基因，ER應激上調其表達和分泌，但它與炎癥的關系未見報道。研究發現：在甲基化牛血清白蛋白誘導的兔關節炎及大鼠佐劑性關節炎模型上，關節局部炎癥能誘導ER應激，上調ARMET表達，并且滑膜組織中表達ARMET的細胞類型主要為成纖維樣滑膜細胞；關節炎癥能誘導ARMET分泌，在炎癥不同時期，外周血中ARMET水平明顯升高，與急性期反應蛋白CRP變化呈正相關；關節炎滑膜組織中ARMET水平與關節炎癥的發展呈負相關。用ARMET siRNA抑制內源性ARMET表達后，細胞增殖能力增強，炎癥因子IL-1β21644；TNF-α34920；達和分泌明顯增加；而重組人ARMET蛋白能劑量依賴性的抑制炎癥滑膜細胞的增殖，降低IL-1β21644；TNF-α30340；表達和分泌。此外，ER應激誘導劑tunicamycin能誘導滑膜細胞中ARMET的核轉移。上述結果提示，關節局部炎癥可誘導ER應激并上調ARMET表達，ARMET的誘導表達對炎性滑膜細胞的過度激活有抑制作用。

關鍵詞：ARMET 內質網應激 滑膜細胞 佐劑性關節炎

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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