STUDIES ON THE MECHANISM OF SIGNAL TRANSDUCTION THROUGH HYALURONAN RECEPTORS IN HUMAN SYNOVIAL CELLS OF RHEUMATOID ARTHRITIS.

类风湿性关节炎人类滑膜细胞中透明质酸受体信号转导机制的研究。

• 批准号: 09672245
• 负责人: TAMOTO Koichi
• 金额: $ 1.98万
• 依托单位: HEALTH SCIENCES UNIVERSITY OF HOKKAIDO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672245/
• 关键词: hyaluronan; rheumatoid arthritis; synovial cells; fibroblast; hyaluronan receptor; cyclooxygenase 2; prostaglandine E2; monoclonal antibody; ヒアルロン酸レセプター; プロスタグランジンE2

The spontaneous and IL-lalpha-induced prostaglandin E2 (PGE2) generation in human synovial cells from a patient of rheumatoid arthritis (RASCs) were inhibited by high-molecular-weighthyaluronates (HAs) in a molecular-weight-and concentration-dependent maimer. On the otherhand, HAs with lower molecular sizes than 4x1O^4 Da, especially HA oligomers, rather augmented PGE2 generation. The inhibitory and stimulatory effects of HAs on PGE2 generation were due to the signaling events via HA receptor that control negatively or positively the transcription of COX2 gene. In noninflammatory cells, human dermal fibroblast (HDF), HA oligomers failed to induce the expression of COX2 protein, suggessting that certain inflammatory signals may be required for the action of HA oligomers. When HA-binding proteins were isolatedfrom RASC and HDF, a various types of membrane proteins that did not required Ca^<2+> and Mg^<2+> for their HA-binding ability were identified. Newly prepared monoclonal antibodies directed to these HA-binding proteins never inhibited the expression of COX2 protein but some of the antibodies rather induced the expression of COX2 protein in RASC and HDF.These results suggest that the extent of cross-linkage of HA receptors that mediated by a single HA molecule may determine the property of intracellular signals that regulate the transcription of COX2 gene. The binding of HA oligomer to a single HA receptor molecule may not be enough to generate signals that may induce the expression of COX2 protein. We could not have a evidence that the elevation of concentration in intracellular free calcium ion and the activation of MAP kinase are involved in the signaling pathway through HA receptors which regulates the transcription of COX2 gene.

类风湿关节炎（RA）患者滑膜细胞自发和IL-1 α诱导的前列腺素E_2（PGE_2）生成可被高分子量的胸腺素酸酯（HA）以分子量和浓度依赖性方式抑制。另一方面，分子量小于4 × 10^4 Da的HA，尤其是HA寡聚体，反而增加了PGE 2的产生。HA对PGE 2的抑制和促进作用是通过HA受体的信号转导作用负或正调控COX 2基因的转录。在非炎症细胞中，人皮肤成纤维细胞（HDF），HA寡聚体未能诱导COX 2蛋白的表达，这表明HA寡聚体的作用可能需要某些炎症信号。当从RASC和HDF中分离HA结合蛋白时，鉴定出了各种类型的膜蛋白，它们不需要Ca^<2+>和Mg^<2+>就具有HA结合能力。针对这些HA结合蛋白的单克隆抗体在RASC和HDF中均不抑制COX 2蛋白的表达，但有些抗体却诱导COX 2蛋白的表达，这些结果表明，由单个HA分子介导的HA受体交联程度可能决定了调控COX 2基因转录的细胞内信号的性质。HA寡聚体与单个HA受体分子的结合可能不足以产生可诱导COX 2蛋白表达的信号。目前尚没有证据表明细胞内游离钙离子浓度的升高和MAP激酶的激活参与了通过HA受体调节COX 2基因转录的信号通路。

项目成果

Koichi Sato, Naoya Murata, Junko Kon, Hideaki Tomura, Hiromi Nochi, Koichi Tamoto, Mizuho Osada, Hideo Ohta, Yukiko Tokumitsu, Michio Ui, and Fumikazu Okajima: "Downregulation of mRNA expression of Edg-3, a putative sphingosine 1-phosphate receptor couple

Koichi Sato、Naoya Murata、Junko Kon、Hideaki Tomura、Hiromi Nochi、Koichi Tamoto、Mizuho Osada、Hideo Ohta、Yukiko Tokumitsu、Michio Ui 和 Fumikazu Okajima：“Edg-3（一种假定的 1-磷酸鞘氨醇）的 mRNA 表达下调

Fumikazu Okajima: "Stimulatory and inhibitory actions of lysophoshatidylcholine,sdepending on its fatty acid residue, on the phospholipase C-Ca^<2+> system in HL-60 leukemia cells." Biochem.J.336. 491-500 (1998)

Fumikazu Okajima：“溶血磷脂酰胆碱对 HL-60 白血病细胞中磷脂酶 C-Ca^2> 系统的刺激和抑制作用取决于其脂肪酸残基。”

Fumikazu Okajima, Koichi Sato, Hideaki Tomura, Atsusi Kuwabara, Hiromi Nochi, Koichi Tamoto, Yoichi Kondo, Yukiko Tokumitsu, and Michio Ui: "Stimulatory and inhibitory actions of lysophosphatidylcholine, depending on its fatty acid residue, on the phospho

Fumikazu Okajima、Koichi Sato、Hideaki Tomura、Atsusi Kuwabara、Hiromi Nochi、Koichi Tamoto、Yoichi Kondo、Yukiko Tokumitsu 和 Michio Ui：“溶血磷脂酰胆碱根据其脂肪酸残基对磷酸盐的刺激和抑制作用

Fumikazu Okajma: "Stimulatory and inhibitory actions of lysophosphatidylcholine,depending on its fatty acid residue,on the phaspholipare C/Ca^<2+> systemin in HL60 leukemia cells." Biochem.J.336. 491-500 (1998)

Fumikazu Okajma：“溶血磷脂酰胆碱对 HL60 白血病细胞中磷脂酰胆碱 C/Ca^2 系统素的刺激和抑制作用取决于其脂肪酸残基。”

Hiromi Nochi, Nobuyuki Nagasaki, Yasumitsu Shimada, Yoki Mori, and Koichi Tamoto: "Possible role of CR3 in the mechanism of zymosan phagocytosis by guinea pig macrophages." (in preparation).

Hiromi Nochi、Nobuyuki Nagasaki、Yasumitsu Shimada、Yoki Mori 和 Koichi Tamoto：“CR3 在豚鼠巨噬细胞吞噬酵母聚糖的机制中的可能作用。”