Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9

Authors

  • Azuma Watanabe,

    1. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT
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  • Ardeshir Hashmi,

    1. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT
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  • Dawidson Assis Gomes,

    1. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT
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  • Terrence Town,

    1. Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT
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  • Abdallah Badou,

    1. Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT
    Current affiliation:
    1. Université Cadi Ayyad, Faculté polydisciplinaire Safi, Morocco
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  • Richard Anthony Flavell,

    1. Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT
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  • Wajahat Zafar Mehal

    Corresponding author
    1. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT
    2. Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT
    • Section of Digestive Diseases, Yale University, 333 Cedar Street, 1080 LMP, P.O. Box 208019, New Haven, CT 06520-8019===

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    • fax: 203-785-7273


  • Potential conflict of interest: Nothing to report.

Abstract

Apoptosis of hepatocytes results in the development of liver fibrosis, but the molecular signals mediating this are poorly understood. Degradation and modification of nuclear DNA is a central feature of apoptosis, and DNA from apoptotic mammalian cells is known to activate immune cells via Toll-like receptor 9 (TLR9). We tested if DNA from apoptotic hepatocytes can induce hepatic stellate cell (HSC) differentiation. Our data show that apoptotic hepatocyte DNA and cytidine-phosphate-guanosine oligonucleotides induced up-regulation of transforming growth factor β1 and collagen 1 messenger RNA both in the human HSC line LX-2 and in primary mouse HSCs. These effects were opposed by TLR9 antagonists. We have recently shown that adenosine inhibits HSC chemotaxis, and we now show that apoptotic hepatocyte DNA also inhibits platelet-derived growth factor (PDGF)-mediated HSC chemotaxis. Inhibition of HSC chemotaxis by PDGF was blocked by TLR9 antagonists, and was absent in primary HSCs from mice deficient in TLR9 or the TLR adaptor molecule MyD88. Stimulation of TLR9 on HSCs blocked signaling by the PDGF signaling molecule inositol 1,4,5-triphosphate and reduced PDGF-mediated increase in cytosolic Ca2+. Conclusion: DNA from apoptotic hepatocytes acts as an important mediator of HSC differentiation by (1) providing a stop signal to mobile HSCs when they have reached an area of apoptosing hepatocytes and (2) inducing a stationary phenotype-associated up-regulation of collagen production. (HEPATOLOGY 2007.)

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