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Fibroblast growth factor 2 (FGF2) regulates cytoglobin expression and activation of human hepatic stellate cells via JNK signaling.
Sato-Matsubara, Misako; Matsubara, Tsutomu; Daikoku, Atsuko; Okina, Yoshinori; Longato, Lisa; Rombouts, Krista; Thuy, Le Thi Thanh; Adachi, Jun; Tomonaga, Takeshi; Ikeda, Kazuo; Yoshizato, Katsutoshi; Pinzani, Massimo; Kawada, Norifumi.
Afiliação
  • Sato-Matsubara M; From the Department of Hepatology.
  • Matsubara T; Endowed Laboratory of Synthetic Biology, and.
  • Daikoku A; Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
  • Okina Y; From the Department of Hepatology.
  • Longato L; From the Department of Hepatology.
  • Rombouts K; the Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free, London NW3 2PF, United Kingdom, and.
  • Thuy LTT; the Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free, London NW3 2PF, United Kingdom, and.
  • Adachi J; From the Department of Hepatology.
  • Tomonaga T; the Laboratory of Proteome Research, Proteome Research Center, National Institute of Biomedical Innovation, Osaka 567-0085, Japan.
  • Ikeda K; the Laboratory of Proteome Research, Proteome Research Center, National Institute of Biomedical Innovation, Osaka 567-0085, Japan.
  • Yoshizato K; Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.
  • Pinzani M; Endowed Laboratory of Synthetic Biology, and.
  • Kawada N; the Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free, London NW3 2PF, United Kingdom, and.
J Biol Chem ; 292(46): 18961-18972, 2017 11 17.
Article em En | MEDLINE | ID: mdl-28916723
Cytoglobin (CYGB) belongs to the mammalian globin family and is exclusively expressed in hepatic stellate cells (HSCs) in the liver. In addition to its gas-binding ability, CYGB is relevant to hepatic inflammation, fibrosis, and cancer because of its anti-oxidative properties; however, the regulation of CYGB gene expression remains unknown. Here, we sought to identify factors that induce CYGB expression in HSCs and to clarify the molecular mechanism involved. We used the human HSC cell line HHSteC and primary human HSCs isolated from intact human liver tissues. In HHSteC cells, treatment with a culture supplement solution that included fibroblast growth factor 2 (FGF2) increased CYGB expression with concomitant and time-dependent α-smooth muscle actin (αSMA) down-regulation. We found that FGF2 is a key factor in inducing the alteration in both CYGB and αSMA expression in HHSteCs and primary HSCs and that FGF2 triggered the rapid phosphorylation of both c-Jun N-terminal kinase (JNK) and c-JUN. Both the JNK inhibitor PS600125 and transfection of c-JUN-targeting siRNA abrogated FGF2-mediated CYGB induction, and conversely, c-JUN overexpression induced CYGB and reduced αSMA expression. Chromatin immunoprecipitation analyses revealed that upon FGF2 stimulation, phospho-c-JUN bound to its consensus motif (5'-TGA(C/G)TCA), located -218 to -222 bases from the transcription initiation site in the CYGB promoter. Of note, in bile duct-ligated mice, FGF2 administration ameliorated liver fibrosis and significantly reduced HSC activation. In conclusion, FGF2 triggers CYGB gene expression and deactivation of myofibroblastic human HSCs, indicating that FGF2 has therapeutic potential for managing liver fibrosis.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Globinas / Ativação Transcricional / Fator 2 de Crescimento de Fibroblastos / Sistema de Sinalização das MAP Quinases / Células Estreladas do Fígado Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Globinas / Ativação Transcricional / Fator 2 de Crescimento de Fibroblastos / Sistema de Sinalização das MAP Quinases / Células Estreladas do Fígado Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article