Gastroenterology
Volume 138, Issue 2 , Pages 671-681.e2, February 2010

Silymarin Inhibits In Vitro T-Cell Proliferation and Cytokine Production in Hepatitis C Virus Infection

  • Chihiro Morishima

      Affiliations

    • Division of Virology, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
    • Corresponding Author InformationReprint requests Address requests for reprints to: Chihiro Morishima, MD, Department of Laboratory Medicine, University of Washington, Box 359743, Seattle, Washington 98104. fax: (206) 897-4312
    • ,
  • Margaret C. Shuhart

      Affiliations

    • Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
    • ,
  • Chia C. Wang

      Affiliations

    • Division of Infectious Diseases, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
    • ,
  • Denise M. Paschal

      Affiliations

    • Division of Virology, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
    • ,
  • Minjun C. Apodaca

      Affiliations

    • Division of Virology, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
    • ,
  • Yanze Liu

      Affiliations

    • Department of Psychiatry, McLean General Hospital, Harvard Medical School, Boston, Massachusetts
    • ,
  • Derek D. Sloan

      Affiliations

    • Division of Virology, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
    • Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Tyler N. Graf

      Affiliations

    • Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, North Carolina
    • ,
  • Nicholas H. Oberlies

      Affiliations

    • Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, North Carolina
    • ,
  • David Y.–W. Lee

      Affiliations

    • Department of Psychiatry, McLean General Hospital, Harvard Medical School, Boston, Massachusetts
    • ,
  • Keith R. Jerome

      Affiliations

    • Division of Virology, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
    • Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington
    • ,
  • Stephen J. Polyak

      Affiliations

    • Division of Virology, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington
    • Department of Global Health, University of Washington School of Medicine, Seattle, Washington

Received 28 October 2008; accepted 15 September 2009. published online 25 September 2009.

Background & Aims

Silymarin, an extract from the seeds of the milk thistle plant Silybum marianum, has been used for centuries for the treatment of chronic liver diseases. Despite common use by patients with hepatitis C in the United States, its clinical efficacy remains uncertain. The goal of this study was to determine whether silymarin has in vitro effects on immune function that might have implications for its potential effect on hepatitis C virus (HCV)-induced liver disease.

Methods

Freshly isolated peripheral blood mononuclear cells (PBMC) and T cells from HCV-infected and uninfected subjects were tested in vitro for responses to nonspecific and antigenic stimulation in the presence and absence of a standardized preparation of silymarin (MK001).

Results

Minimal MK001 toxicity on PBMC was found at concentrations between 5 and 40 μg/mL. MK001 dose dependently inhibited the proliferation and secretion of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-2 by PBMC stimulated with anti-CD3. In addition, MK001 inhibited proliferation by CD4+ T cells to HCV, Candida, and tetanus protein antigens and by HLA-A2/HCV 1406–1415-specific CD8+ T cells to allogeneic stimulation. MK001 inhibited T-cell TNF-α and IFN-γ cytokine secretion to tetanus and Candida protein antigens. Finally, MK001 inhibited nuclear factor-κB transcriptional activation after T-cell receptor-mediated stimulation of Jurkat T cells, consistent with its ability to inhibit Jurkat T-cell proliferation and secretion of IL-2.

Conclusions

Silymarin's ability to inhibit the proliferation and proinflammatory cytokine secretion of T cells, combined with its previously described antiviral effect, suggests a possible mechanism of action that could lead to clinical benefit during HCV infection.

Abbreviations used in this paper: CFSE, carboxyfluoroscein succinimidyl ester, DMSO, dimethyl sulfoxide, ELISA, enzyme-linked immunosorbent assay, HCV, hepatitis C virus, IFN-γ, interferon-γ, PBMC, peripheral blood mononuclear cells, PHA, phytohemagglutinin, PMA, phorbol myristate acetate, rh, recombinant human, TNF-α, tumor necrosis factor-α

 

 Conflicts of interest The authors disclose no conflicts.

 Funding Supported by grant R21 AT002895 from the National Center for Complementary and Alternative Medicines/National Institutes of Health (to S.J.P.) and by grant R01 CA104286 from the National Cancer Institute/NIH for the isolation of pure compounds from milk thistle (to T.N.G./N.H.O.); however, study sponsors had no role in the collection, analysis, or interpretation of the data in this manuscript.

PII: S0016-5085(09)01662-X

doi:10.1053/j.gastro.2009.09.021

Gastroenterology
Volume 138, Issue 2 , Pages 671-681.e2, February 2010