Abnormal expression of phospholipases A_2 and human diseases

磷脂酶A_2的异常表达与人类疾病

• 批准号: 07307028
• 负责人: KUDO Ichiro
• 金额: $ 1.86万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07307028/
• 关键词: phospholipases A_2; nephritis; multi-organ dysfunction; diabetes; breast carcinoma; PAF-acetylhydrolase; immediate allergy; ホスホリパーゼA_2; 乳ガン細胞

We have examined the expression and function of phospholipase A_2 (PLA_2) isoforms that are implicated in arachidonate metabolism and their possible prticipation in human diseases.1. Analysis of PLA_2 isoforms(1) Cytosolic PLA_2 (cPLA_2) was expressed in various mamalian cells ubiquitously and consititutively. It was essential for the immediate phase of arachidonate methabolism that occurs within a few minutes after cell activation. In most cases, arachidonic acid released by cPLA_2 in the immediate phase was converted to prostanoids by constitutive cyclooxygenase COX-1.(2) Secretory type II PLA_2 was induced in various types of cell in response to proinflammatory stimuli. This enzyme was functionally coupled with inducible COX-2 to provide delayd phase of prostanoid generation that lasts for several hours.(3) Two novel secretory PLA_2 members, type IIC and V,were cloned from testis and heart, respectively. Recombinant expression of these enzymes was carried out. the expression and function of these PLA_2s in mammalian cells are currently under investigation.2. Implication of PLA_2 isozymes in human diseases(1) Multiple organ dysfunction : Gut ishchemia/reperfusion in the rat, used as a model system, caused lung injury via a mechanism which involved type II PLA_2.(2) Rheumatoid arthritis : There was significant correlation between IL-6 and type II PLA_2 in the synovial fluid of patients with rheumatoid arthritis.(3) Diabetes : Platelets from patients with diabetes contained higher level of cPLA_2 than normal littermates.(4) Cancer : Several lung carcinomas were found to contain some unknown cPLA_2-inhibitory substances.

我们研究了磷脂酶A_2（PLA_2）亚型的表达和功能，它们与花生四烯酸代谢有关，并可能与人类疾病有关。PLA_2亚型分析（1）胞浆PLA_2（cPLA_2）在多种哺乳动物细胞中广泛表达。这是必不可少的花生四烯酸甲酯，发生在细胞活化后几分钟内的即时阶段。在大多数情况下，cPLA_2释放的花生四烯酸在立即相被组成型环氧合酶考克斯-1转化为前列腺素类。(2)促炎刺激可诱导多种类型细胞分泌II型PLA_2。该酶与诱导型考克斯-2功能性偶联，以提供持续数小时的前列腺素类生成的延迟相。(3)分别从睾丸和心脏中克隆到两个新的分泌型PLA_2成员，即IIC型和V型。进行这些酶的重组表达。这些PLA_2在哺乳动物细胞中的表达和功能目前正在研究中。PLA_2同工酶在人类疾病中的意义（1）多器官功能障碍：以大鼠肠缺血再灌注为模型，通过II型PLA_2引起肺损伤。(2)类风湿性关节炎患者关节液中IL-6与Ⅱ型PLA_2水平呈显著相关。(3)糖尿病患者血浆中cPLA_2含量高于同窝正常人。(4)癌症：发现几种肺癌含有一些未知的cPLA_2抑制物质。

项目成果

Murakami,M.: "Type II secretory phsopholipase A_2 associated with cell surfaces via C-terminal heparin-binding lysine residues angments stimulus-initiated delayed prostaglandin generation." J.Biol.Chem.271. 30041-30051 (1996)

Murakami,M.：“II 型分泌性磷脂酶 A_2 通过 C 末端肝素结合赖氨酸残基与细胞表面相关，并刺激刺激引发的前列腺素生成延迟。”

Ashraf,M.M.D.: "Crosslinking of Fc,RI induced expression of cyclooxygenase-2 and aftendanl delayed prostaglandin generation requiring interleukin-10 and interleukin-1β 1in mouse cultured mast cells." Biochem.J.320. 965-973 (1996)

Ashraf，M.M.D.：“在小鼠培养的肥大细胞中，Fc、RI 的交联诱导了环氧合酶 2 和 aftendanl 的表达，延迟了需要白细胞介素 10 和白细胞介素 1β 1 的前列腺素生成。Biochem.J.320 (1996)。”

Ashraf, M.M.D.et al.: "Type II phospholipase A_2 is linked to cyclooxygenase-2-mediated delayd prostaglandin D_2 generation by cultured mouse mast cells following Fc_<epsilon>RI- and cytokine-dependent activation." Biochem.Biophys.Res.Commun.229. 726-732

Ashraf, M.M.D.等人：“II 型磷脂酶 A_2 与培养的小鼠肥大细胞在 Fc_<ε>RI 和细胞因子依赖性激活后延迟产生前列腺素 D_2 相关。”

koike,K: "Phospholipase A_2 in inflamed tissues and inflammatory exudates.21GC06:Prog.Surgery" (in press). (1997)

小池，K：“发炎组织和炎症渗出物中的磷脂酶 A_2。21GC06：Prog.Surgery”（正在印刷中）。

Koike,K.: "Intestinal ishchemia and type II phospholipase A_2." J.Jpn.Surg.Soc.97. 823 (1995)

Koike,K.：“肠缺血和 II 型磷脂酶 A_2。”