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Research ArticleCELLULAR AND MOLECULAR

Signaling Mechanisms Involved in Protease-Activated Receptor-1-Mediated Interleukin-6 Production by Human Gingival Fibroblasts

Nobuhisa Tanaka, Takao Morita, Akihiro Nezu, Akihiko Tanimura, Itaru Mizoguchi and Yosuke Tojyo
Journal of Pharmacology and Experimental Therapeutics November 2004, 311 (2) 778-786; DOI: https://doi.org/10.1124/jpet.104.068569
Nobuhisa Tanaka
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Takao Morita
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Akihiro Nezu
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Akihiko Tanimura
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Itaru Mizoguchi
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Yosuke Tojyo
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Abstract

Human gingival fibroblasts (HGFs) express protease-activated receptor-1 (PAR-1) at high levels. In cultured HGFs, we studied the signaling pathway of thrombin-induced interleukin-6 (IL-6) production. The PAR-1 agonist peptide SFLLRN mimicked the thrombin-induced IL-6 production in the presence of amastatin, an aminopeptidase inhibitor. Thrombin or a combination of SFLLRN and amastatin also strikingly induced the expression of IL-6 mRNA. Although continuous exposure of HGFs to thrombin rapidly desensitized Ca2+ signaling, the cells did not lose their ability to produce IL-6 in response to thrombin. Similarly, although treatment of HGFs with BAPTA-AM [1,2-bis(O-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester], an intracellular Ca2+ chelator, markedly attenuated the thrombin-induced increase in intracellular Ca2+ concentration, the same treatment did not suppress the thrombin-induced IL-6 production. However, thrombin-induced IL-6 production was strongly inhibited by the p38 mitogen-activated protein (MAP) kinase and tyrosine kinase inhibitors, and Western blotting analyses showed that thrombin stimulates p38 MAP kinase phosphorylation. Specific inhibitors that inhibit extracellular signal-regulated kinase 1/2 kinase, phosphatidylinositol 3-kinase, and RhoA kinase also partially suppressed the thrombin-induced IL-6 production, but the effects were smaller than those of the p38 MAP and tyrosine kinase inhibitors. Thus, thrombin induces HGFs to produce IL-6 by activating PAR-1, and the tyrosine kinase- and p38 MAP kinase-dependent pathways, rather than the Ca2+ signaling pathway, may play a crucial role in the IL-6 production.

Footnotes

  • This study was partially supported by the Academic Science Frontier Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

  • doi:10.1124/jpet.104.068569.

  • ABBREVIATIONS: PAR, protease-activated receptor; TB thrombin; HGF, human gingival fibroblast; IL, interleukin; MAP kinase, mitogen-activated protein kinase; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; PD98059, 2′-amino-3′-methoxyflavone; LPS, lipopolysaccharide; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-methylthio)butadiene; SB 202474, 4-(ethyl)-2-(4-methoxyphenyl)-5-(4-pyridyl)-1H-imidazole; Y-27632, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecanboxamide; SB 202190, 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole; Ro-31-8220, bisindolylmaleimide IX, 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl) maleimide; BAPTA-AM, 1,2-bis(O-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid-acetoxymethyl ester; α-MEM, α-minimum essential medium; ELISA, enzyme-linked immunosorbent assay; RT, reverse transcriptase; PCR, polymerase chain reaction; DMSO, dimethyl sulfoxide; ERK1/2, extracellular signal-regulated kinase 1/2; PI, phosphatidylinositol; PKC, protein kinase C.

    • Received March 18, 2004.
    • Accepted June 21, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 2
1 Nov 2004
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Research ArticleCELLULAR AND MOLECULAR

Signaling Mechanisms Involved in Protease-Activated Receptor-1-Mediated Interleukin-6 Production by Human Gingival Fibroblasts

Nobuhisa Tanaka, Takao Morita, Akihiro Nezu, Akihiko Tanimura, Itaru Mizoguchi and Yosuke Tojyo
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 778-786; DOI: https://doi.org/10.1124/jpet.104.068569

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Research ArticleCELLULAR AND MOLECULAR

Signaling Mechanisms Involved in Protease-Activated Receptor-1-Mediated Interleukin-6 Production by Human Gingival Fibroblasts

Nobuhisa Tanaka, Takao Morita, Akihiro Nezu, Akihiko Tanimura, Itaru Mizoguchi and Yosuke Tojyo
Journal of Pharmacology and Experimental Therapeutics November 1, 2004, 311 (2) 778-786; DOI: https://doi.org/10.1124/jpet.104.068569
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