Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes |
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Authors: | Safadi Rifaat Ohta Masayuki Alvarez Carlos E Fiel M Isabel Bansal Meena Mehal Wajahat Z Friedman Scott L |
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Affiliation: | Division of Liver Diseases, The Mount Sinai School of Medicine, New York, New York, USA. |
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Abstract: | 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. |
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Keywords: | α-SMA, α-smooth muscle actin CCl4, carbon tetrachloride CTGF, connective tissue growth factor FACS, fluorescence-activated cell sorter ICAM-1, intercellular adhesion molecule-1 IL, interleukin rIL, rat interleukin MMP-2, matrix metalloproteinase-2 PDGF, platelet-derived growth factor SCID, severe combined immunodeficiency TAA, thioacetamide TCR, T-cell receptor TG, transgenic TGF, transforming growth factor |
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