Lethal hepatitis after gene transfer of IL-4 in the liver is independent of immune responses and dependent on apoptosis of hepatocytes: a rodent model of IL-4-induced hepatitis.

Abstract

The putative role of IL-4 in human and animal models of hepatitis has not yet been directly determined. We now report that direct expression of IL-4 in the liver of rats or mice using recombinant adenoviruses coding for rat or mouse IL-4 (AdrIL-4 and AdmIL-4, respectively) results in a lethal, dose-dependent hepatitis. The hepatitis induced by IL-4 was characterized by hepatocyte apoptosis and a massive monocyte/macrophage infiltrate. IL-4-induced hepatitis was independent of T cell-mediated immune responses. Hepatitis occurred even after gene transfer of IL-4 into nude rats, CD8-depleted rats, cyclosporine A-treated rats, or recombinase-activating gene 2(-/-) immunodeficient mice. Peripheral depletion of leukocytes using high doses of cyclophosphamide, and/or the specific depletion of liver macrophages with liposome-encapsulated dichloromethylene diphosphonate in rats did not block lethal IL-4-induced hepatitis. Direct transduction of hepatocytes with adenoviruses was not essential, since injection of AdrIL-4 into the hind limb induced an identical hepatitis. Finally, primary rat hepatocytes in culture also showed apoptosis when cultured in the presence of rIL-4. IL-4-dependent hepatitis was associated with increases in the intrahepatic levels of IFN-gamma, TNF-alpha, and Fas ligand. Administration of AdmIL-4 to IFN-gamma, TNF-alpha receptor type I, or TNF-alpha receptor type II knockout mice also resulted in lethal hepatitis, whereas a moderate protection was observed in Fas-deficient lpr mice. IL-4-dependent hepatocyte apoptosis could be abolished by treatment with caspase inhibitory peptides. Our results thus demonstrate that IL-4 causes hepatocyte apoptosis, which is only partially dependent on the activation of Apo-1-Fas signaling and is largely independent of any immune cells in the liver.

• Authors: C Guillot, H Coathalem, J Chetritt, A David, P Lowenstein, E Gilbert, L Tesson, N van Rooijen, M C Cuturi, J P Soulillou, I Anegon
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 166 Issue 8 Pg. 5225-35 (Apr 15 2001) ISSN: 0022-1767 [Print] United States
• PMID: 11290807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Caspase Inhibitors
• Cysteine Proteinase Inhibitors
• FASLG protein, human
• Fas Ligand Protein
• Fasl protein, mouse
• Faslg protein, rat
• Membrane Glycoproteins
• N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
• Tumor Necrosis Factor-alpha
• Interleukin-4
• Interferon-gamma

Topics

• Acute Disease
• Adenoviridae (genetics, immunology)
• Amino Acid Chloromethyl Ketones (therapeutic use)
• Animals
• Apoptosis (drug effects, immunology)
• Caspase Inhibitors
• Cell Movement (immunology)
• Cysteine Proteinase Inhibitors (therapeutic use)
• Fas Ligand Protein
• Gene Transfer Techniques
• Genetic Vectors (administration & dosage, immunology)
• Hepatitis, Viral, Animal (genetics, immunology, mortality, pathology)
• Hepatocytes (immunology, pathology)
• Immunity, Cellular (genetics)
• Interferon-gamma (biosynthesis)
• Interleukin-4 (administration & dosage, biosynthesis, genetics, physiology)
• Kupffer Cells (immunology, virology)
• Leukocytes (pathology)
• Liver (drug effects, enzymology, immunology, pathology)
• Male
• Membrane Glycoproteins (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• Rats
• Rats, Nude
• Rats, Wistar
• T-Lymphocytes (immunology, virology)
• Transduction, Genetic
• Tumor Necrosis Factor-alpha (biosynthesis)