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Regulation of neutrophil apoptosis in rheumatoid arthritis

类风湿性关节炎中性粒细胞凋亡的调节

基本信息

批准号：
10670423
负责人：
AKAHOSHI Tohru
金额：
$ 1.79万
依托单位：
KITASATO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670423/
关键词：
rheumatoid arthritis neutrophils apoptosis PGE_2 炎症滑膜細胞

项目摘要

Infiltration of neutrophils into the inflamed joints is a characteristic feature of rheumatoid arthritis (RA). Accumulated neutrophils play pivotal roles on destruction of the inflamed joints through the elaboration of inflammatory mediators. Neutrophils are short-lived cells and spontaneously die by apoptosis. A number of factors have been shown to modulate spontaneous neutrophil apoptosis. However, the regulatory mechanisms of neutrophil apoptosis in RA have not been elucidated. We investigated the regulatory roles of synovial cell-derived-factors and various anti-rheumatic drugs on neutophil apoptosis. The results obtained in this study are as following. (1) Pro-inflammatory cytokines (IL-1, TNF-α) produce soluble factor (s) capable of inhibiting spontaneous neutrophil apoptosis. (2) GM-CSF is a major factor for this activity. (3) A novel inhibitory factor for neutrophil apoptosis (MW about 25 Kd) has been found. (4) PGE2 prevented neutrophil apoptosis through the binding to the receptors (EP4 and EP2) on neutrophils. On the other hand, EP3 agonist rapidly promoted unique death of neutrophils resembling to apoptosis. (5) Among the anti-rheumatic drugs examined, sulfasalazine rapidly promoted neutrophil apoptosis and lipophilic gold complex (auranofin) also modulated cellular death. These findings indicate that joint inflammation potentially elongates neutrophil survival by inhibiting apoptosis and the drugs used in the treatment of RA promote neutrophil death by inducing apoptosis.

中性粒细胞浸润发炎关节是类风湿性关节炎（RA）的一个特征。累积的中性粒细胞通过炎症介质的产生，在破坏发炎关节方面发挥着关键作用。中性粒细胞是短命细胞，会因细胞凋亡而自发死亡。许多因素已被证明可以调节自发性中性粒细胞凋亡。然而，RA中中性粒细胞凋亡的调节机制尚未阐明。我们研究了滑膜细胞衍生因子和各种抗风湿药物对中性粒细胞凋亡的调节作用。本研究获得的结果如下。 (1)促炎细胞因子(IL-1、TNF-α)产生能够抑制自发性中性粒细胞凋亡的可溶性因子。 (2) GM-CSF是该活动的主要因素。 (3)发现了一种新的中性粒细胞凋亡抑制因子(MW约25Kd)。 (4)PGE2通过与中性粒细胞上的受体(EP4和EP2)结合来阻止中性粒细胞凋亡。另一方面，EP3激动剂迅速促进中性粒细胞的独特死亡，类似于细胞凋亡。 (5)在所检测的抗风湿药物中，柳氮磺吡啶迅速促进中性粒细胞凋亡，亲脂性金复合物（金诺芬）也调节细胞死亡。这些发现表明，关节炎症可能通过抑制细胞凋亡来延长中性粒细胞的存活时间，而用于治疗 RA 的药物则通过诱导细胞凋亡来促进中性粒细胞死亡。