Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes

Gastroenterology. 2004 Sep;127(3):870-82. doi: 10.1053/j.gastro.2004.04.062.


Backgrounds & aims: Immunomodulatory cytokines, including interleukin-10 (IL-10), may mediate hepatic fibrosis.

Methods: We generated transgenic (TG) mice with hepatocyte expression of rat IL-10 (rIL-10) to assess its impact on lymphocyte subsets and activation of hepatic stellate cells following liver injury from carbon tetrachloride (CCl 4 ) or thioacetamide (TAA).

Results: Fibrosis was reduced in the TG animals in both models, which was not explained solely by differences in liver injury. By fluorescence-activated cell sorter (FACS), there were less CD4+ T cells in naive TG mice, and, following fibrosis induction, CD4+ T cells decreased only in wild-type (WT) mice, whereas increases in CD8+ T cells seen in WT animals were significantly attenuated in TG mice. Subtotal irradiation diminished fibrosis equally in both WT and TG groups, suggesting that rIL-10's antifibrotic effect was lymphocyte mediated. To assess the role of lymphocytes on stellate cell activation, either whole splenic lymphocytes, CD4+, or CD8+ T-cell subsets from WT animals with CCl 4 fibrosis were adoptively transferred to severe combined immunodeficiency (SCID) recipients, which led to stellate cell activation and fibrogenic stimulation as assessed by expression of transforming growth factor (TGF)-beta1 and collagen I messenger RNA (mRNA) and by immunoblot of alpha-smooth muscle actin. Moreover, serum aminotransferase levels and stellate cell activation mRNA were significantly higher among the CD8+ T-cell recipients.

Conclusions: Transgenic expression of rIL-10 in liver leads to reduced fibrosis and alterations in liver lymphocyte subsets both in untreated liver and following fibrosis induction. In this model, fibrosis may be a CD8+ T-cell-mediated disease that is attenuated by rIL-10.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / radiation effects
  • Hepatocytes / immunology
  • Hepatocytes / pathology
  • Interleukin-10 / immunology*
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / radiotherapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Animal


  • Interleukin-10