Cytokine Regulation of Hepatic Stellate Cells in Liver Fibrosis

Authors

  • Hidekazu Tsukamoto

    Corresponding author
    1. Departments of Medicine and Pathology, University of Southern California School of Medicine, Los Angeles, California; and Department of Veterans Affairs Medical Center, Sepulveda, California.
      Reprint requests: Hide Tsukanzoto, D.V.M., Ph.D., Department of Medicine, University of Southern California School of Medicine, 2011 Zonal Avetzire, HMR-101. Los Angeles, CA 90033; E-mail: htsukamo@hsc.usc.edu
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  • This study was supported by U.S. Public Health Service Grants R37 AA06603 and P50AA11999, and by the Department of Veterans Affairs.

Reprint requests: Hide Tsukanzoto, D.V.M., Ph.D., Department of Medicine, University of Southern California School of Medicine, 2011 Zonal Avetzire, HMR-101. Los Angeles, CA 90033; E-mail: htsukamo@hsc.usc.edu

Abstract

Cytokines constitute a major class of mediators responsible for “activation” of hepatic stellate cells (HSCs) in vitro and in vivo. They are largely divided into mitogenic (transforming growth factor-α, platelet-derived growth factor, interleukin-1, tumor necrosis factor-α, and insulin-like growth factor) and fibrogenic (transforming growth factor-β and interleukin-6) cytokines. In addition to their mitogenic (stimulation of cell proliferation) and fibrogenic (induction of matrix proteins) properties, they are also shown to confer in vitro unique cellular changes known to be the key features of HSC “activation,” including loss of vitamin A, stimulation of migration, enhanced cellular contractility, and matrix metalloproteinase and tissue inhibitor of metalloproteinase induction. Potential cellular sources of the cytokines consist of hepatic macrophages, endothelial cells, biliary epithelial cells, lymphocytes, platelets, hepatocytes, and activated HSCs. To better understand the mode of actions and the pathogenetic significance of cytokineskhemokines involved in “activation” of HSCs, the following four questions need to be addressed: (1) What other cytokines are expressed by HSCs to establish critical autocrine stimulation? (2) What are endogenous or exogenous priming factors for HSC stimulation? (3) What is the mechanism of activation for transforming growth factor-β, the pivotal fibrogenic cytokine? (4) How important are HSC-derived proinflammatory mediators in liver fibrosis? This review will discuss these questions, along with the current understanding of the role of cytokines in HSC activation.

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