Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection.
OBJECTIVE
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 microg/mL. MK001 dose dependently inhibited the proliferation and secretion of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, 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-alpha and IFN-gamma cytokine secretion to tetanus and Candida protein antigens. Finally, MK001 inhibited nuclear factor-kappaB 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.
Morishima
Chihiro
C
Division of Virology, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, Washington 98104, USA. chihiro@u.washington.edu
Shuhart
Margaret C
MC
Wang
Chia C
CC
Paschal
Denise M
DM
Apodaca
Minjun C
MC
Liu
Yanze
Y
Sloan
Derek D
DD
Graf
Tyler N
TN
Oberlies
Nicholas H
NH
Lee
David Y-W
DY
Jerome
Keith R
KR
Polyak
Stephen J
SJ
D000975:Antioxidants / Q000494:pharmacology; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus; D006526:Hepatitis C / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012838:Silymarin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D007376:Interleukin-2; D012838:Silymarin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma