Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes.
OBJECTIVE
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.
Safadi
Rifaat
R
Division of Liver Diseases, The Mount Sinai School of Medicine, New York, New York, USA.
Ohta
Masayuki
M
Alvarez
Carlos E
CE
Fiel
M Isabel
MI
Bansal
Meena
M
Mehal
Wajahat Z
WZ
Friedman
Scott L
SL
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000276:immunology*; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal
D016753:Interleukin-10