CCK-8对rTNF-α诱导RSC-364增殖和分泌功能的影响及其信号转导机制的研究
本文选题:缩胆囊素 + 肿瘤坏死因子 ; 参考:《河北医科大学》2006年博士论文
【摘要】: 类风湿关节炎(rheumatoid arthritis RA)的主要病变在关节,在关节内可以看到滑膜组织异常增生、大量炎性细胞浸润以及软骨与骨进行性破坏,在关节外则表现为血管炎。疾病过程综合体现了滑膜组织增生、炎症、自身免疫这三种病理生理过程,它们之间相互作用、相互关联,形成了一个错综复杂的网络机制。成纤维样滑膜细胞(fibroblast-like synoviocytes,FLSs)是从RA滑膜中分离得到的外观类似成纤维细胞的一类滑膜细胞。目前认为,RA FLSs过度增生是造成滑膜增厚的主要原因。FLSs分泌IL-6、IL-8、粒-巨噬细胞集落刺激因子( granulocyte-macrophage colony-stimulating factor,GM-CSF)、前列腺素(prostaglandins,PGs)、基质金属蛋白酶(matrix metalloproteinases,MMPs)以及聚合素酶(aggrecanase)和组织蛋白酶等效应分子,对骨与软骨组织造成侵蚀,FLSs被认为是介导RA关节破坏的主要效应细胞,而TNF-α则是参与FLSs反应的关键性细胞因子。FLSs增殖和分泌在RA发病过程中发挥关键性作用。所以寻找具有调节FLSs上述功能的抗炎制剂已成为研究的热点。八肽胆囊收缩素(cholecystokinin octapeptide,CCK-8)是一种内源性脑肠肽,近年研究表明CCK-8具有抗炎和免疫调节作用。已有报道CCK-8对角叉菜胶诱导的大鼠关节炎有缓解作用。本室先前研究表明,CCK-8对TNF-α诱导胶原性关节炎(collagen-induced arthritis, CIA)大鼠滑膜细胞增殖及大鼠成纤维样滑膜细胞RSC-364增殖和MMP-2、MMP-9分泌皆有抑制作用,提示CCK-8对RA可能具有积极的药理作用。 MMPs和MMPs组织抑制剂(tissue inhibitor of MMPs,TIMPs)系统失衡在RA软骨破坏中起关键作用。CCK-8对MMPs/ TIMPs系统有何影响,尚未见报道。调控MMPs表达及合成的信号转导机制极其复杂,它们往往同时参与RA其它炎性介质的合成及细胞增殖等过程。已知活化蛋白-1(activator protein-1, AP-1)是参与TNF-α诱导RA滑膜细胞MMPs基因表达、增殖及炎症反应的一个十分重要的转录因子。本室前期研究发
[Abstract]:The main lesions of rheumatoid arthritis RAA are in the joint. The synovial tissue is abnormally proliferated, a large number of inflammatory cells infiltrate, and the cartilage and bone are destroyed progressively in the joint, and the vasculitis is seen outside the joint. The disease process embodies three pathophysiological processes of synovial tissue proliferation inflammation and autoimmunity which interact and correlate with each other and form a complicated network mechanism. Fibroblast-like synoviocytes-FLSs (fibroblast-like synoviocytes-FLSs) are fibroblast-like synoviocytes-like synovial cells isolated from RA synoviocytes. At present, it is believed that the excessive proliferation of RA FLSs is the main cause of synovial thickening. FLSs secrete IL-6 and IL-8, granulocyte-macrophage colony-stimulating factor-GM-CSFN, prostaglandins, matrix metalloproteinases, polymerase aggrecanase and cathepsin, etc. FLSs are considered to be the main effector cells involved in the destruction of RA joints, and TNF- 伪 is the key cytokine involved in the FLSs response. FLSs proliferation and secretion play a key role in the pathogenesis of RA. Therefore, the search for anti-inflammatory agents with the function of regulating FLSs has become a hot spot. Cholecystokinin octapeptidein (CCK-8) is an endogenous brain-gut peptide. Recent studies have shown that CCK-8 has anti-inflammatory and immunomodulatory effects. It has been reported that CCK-8 can relieve arthritis induced by carrageenin in rats. Previous studies in our laboratory showed that CCK-8 inhibited the proliferation of synovial cells and the secretion of MMP-2 MMP-9 in fibroblast synoviocytes and collagen-induced synovial cells induced by TNF- 伪 in rats, suggesting that CCK-8 may have a positive pharmacological effect on RA. MMPs and tissue inhibitor of MMPs tissue inhibitor of tissue TIMPs) system imbalance plays a key role in RA cartilage damage. How CCK-8 affects MMPs/ TIMPs system has not been reported. The mechanism of signal transduction regulating MMPs expression and synthesis is very complicated, and they are often involved in the synthesis of other inflammatory mediators of RA and the proliferation of RA cells at the same time. Activator protein-1 (AP-1) is known to be a very important transcription factor involved in the expression, proliferation and inflammatory response of MMPs gene in RA synovial cells induced by TNF- 伪. Prophase research in this room
【学位授予单位】:河北医科大学
【学位级别】:博士
【学位授予年份】:2006
【分类号】:R363
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