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Effect of phorbol ester and platelet-derived growth factor on protein kinase C in rat hepatic stellate cells

Authors

  • Yoshimasa Kobayashi,

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO, USA
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    • *Current address: Yoshimasa Kobayashi, MD, The Second Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-31, Japan.

  • Kim R. Bridle,

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO, USA
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    • Current address: Kim R. Bridle, PhD, Department of Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, QLD 4102, Australia.

  • Grant A. Ramm,

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO, USA
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    • Current address: Grant A. Ramm, PhD, The Hepatic Fibrosis Group, The Queensland Institute of Medical Research, PO Royal Brisbane and Women's Hospital, Brisbane, QLD 4029, Australia.

  • Rosemary O'Neill,

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO, USA
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  • Robert S. Britton,

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO, USA
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  • Bruce R. Bacon

    1. Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO, USA
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Correspondence
Robert S. Britton, PhD, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, 3635 Vista Ave., St Louis, MO 63110-0250, USA
Tel: +1 314 577 8764
Fax: +1 314 577 8125
e-mail: brittonr@slu.edu

Abstract

Background/Aims: Hepatic stellate cells (HSC) play a key role in hepatic fibrogenesis and thus, it is important to understand the intracellular signalling pathways that influence their behaviour. This study investigated the expression and regulation of protein kinase C (PKC) in HSC.

Results: Western blot analysis indicates that rat HSC express at least four PKC isoforms, PKC-α, PKC-δ, PKC-ɛ and PKC-ζ. PKC-α and PKC-ζ were located predominantly in the cytosol and were redistributed to the membrane by the PKC agonist, phorbol 12-myristate 13-acetate (PMA), while PKC-δ and PKC-ɛ were highly membrane-bound and did not undergo translocation by PMA. PKC-α, PKC-δ and PKC-ζ were rapidly downregulated by PMA. However, PKC-ɛ was resistant to downregulation. We also examined phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS), a specific substrate of PKC, as another approach to assess activation of PKC. Platelet-derived growth factor (PDGF) and PMA increased the phosphorylation of MARCKS, suggesting that PDGF can induce PKC activation. PDGF-induced stimulation of extracellular signal-regulated kinase, phosphatidylinositol 3-kinase and p70-S6 kinase was not abrogated by downregulation of PKC-α, PKC-δ and PKC-ζ. Prolonged PKC inhibition did not inhibit the fibrogenic phenotype.

Conclusion: Multiple PKC isoforms are expressed in rat HSC and are differentially regulated by PMA. PDGF activates certain mitogenic signalling pathways independent of PKC-α, PKC-δ and PKC-ζ. Specific PKC isoforms may modulate different cell functions in HSC.

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