Thrombin-Stimulated Proliferation of Cultured Human Synovial Fibroblasts Through Proteolytic Activation of Proteinase-Activated Receptor-1

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概要

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• We examined the mechanism of thrombin on proliferation of synovial fibroblasts obtained from rheumatoid arthritis (RA). Thrombin concentration-dependently induced proliferation of synovial fibroblasts. Proliferation in response to thrombin (10 U/ml) was completely blocked by hirudin. TP367 and TP508, peptides corresponding to 2 noncatalytic regions of thrombin, failed to induce cell proliferation. Thrombin did not induce the production of basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) in synovial fibroblasts. Expression of proteinase-activated receptor (PAR)-1 and PAR-3 mRNAs was observed in synovial fibroblasts. Thrombin and PAR-1 agonist peptide (AP), but not PAR-3 AP, induced intercellular calcium mobilization. PAR-1 AP induced cell proliferation whereas PAR-3 AP and PAR-4 AP had no effect on proliferation. Pertussis toxin (PTX), a Giα protein inhibitor; wortmanin, a PI (phosphatidylinositol) 3-kinase inhibitor; and PD-98059, a specific MEK [mitogen-activated protein (MAK) kinase kinase] inhibitor, inhibited the thrombin-induced cell proliferation. Furthermore, the proliferation of synovial fibroblasts was suppressed by U-73122, a PLC (phospholipase C) inhibitor; 2-APB, an antagonist of InsP3 (inositol 1,4,5-triphosphate) receptor; and GF-109203X, a PKC (protein kinase C) inhibitor. These results suggest that thrombin induces the proliferation of RA synovial fibroblasts through the activation of PAR-1, leading to the PTX-sensitive G proteins – PI3 kinase pathway and PTX-insensitive G proteins – PLC (InsP3 receptor) Ca2+ – PKC branch.

• 社団法人 日本薬理学会の論文
• 2008-09-20

著者

• ABE Kazuki

  Pharmacological Research Department, Minophagen Pharmaceutical CO., LTD.

• INOUE Hideo

  Pharmacological Research Department, Minophagen Pharmaceutical CO., LTD.

• Inoue Hideo

  Pharmacological Research Department Research Laboratory Minophagen Pharmaceutical Co. Ltd.

• Abe Kazuki

  Pharmacological Research Department Research Laboratory Minophagen Pharmaceutical Co. Ltd.

• Inoue Hideo

  Pharmaceutical Research Laboratory Kirin Brewery Co. Ltd.

• FURUHASHI Ikue

  Pharmacological Research Department, Research Laboratory, Minophagen Pharmaceutical Co., Ltd.

• SATO Toshitsugu

  Pharmacological Research Department, Research Laboratory, Minophagen Pharmaceutical Co., Ltd.

• Furuhashi Ikue

  Pharmacological Research Department Research Laboratory Minophagen Pharmaceutical Co. Ltd.

• Sato Toshitsugu

  Pharmacological Research Department Research Laboratory Minophagen Pharmaceutical Co. Ltd.

• Abe Kazuki

  Pharmacological Research Department Minophagen Pharmaceutical Co. Ltd.

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