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

R Safadi, M Ohta, CE Alvarez, MI Fiel, M Bansal… - Gastroenterology, 2004 - Elsevier
R Safadi, M Ohta, CE Alvarez, MI Fiel, M Bansal, WZ Mehal, SL Friedman
Gastroenterology, 2004Elsevier
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 (CCl4) 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) …
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 (CCl4) 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 CCl4 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)-β1 and collagen I messenger RNA (mRNA) and by immunoblot of α-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.
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