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*
Institut National de la Santé et de la Recherche Médicale, Unité 437, Nantes, France;
Molecular Medicine and Gene Therapy Unit, University of Manchester School of Medicine, Manchester, United Kingdom; and
Department of Cell Biology and Immunology, School of Medicine, Free University, Amsterdam, The Netherlands
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-
, TNF-
, and Fas
ligand. Administration of AdmIL-4 to IFN-, TNF- receptor type I,
or TNF- 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.
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