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

The putative role of IL-4 in human and animal models of hepatitis has not y et been directly determined. We now report that direct expression of IL-4 i n the liver of rats or mice using recombinant adenoviruses coding for rat o r 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 hep atocyte apoptosis and a massive monocyte/macrophage infiltrate. IL-4-induce d 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(-/-) immuno deficient mice. Peripheral depletion of leukocytes using high doses of cycl ophosphamide, and/or the specific depletion of liver macrophages with lipos ome-encapsulated dichloromethylene diphosphonate in rats did not block leth al IL-4-induced hepatitis. Direct transduction of hepatocytes with adenovir uses was not essential, since injection of AdrIL-4 into the hind limb induc ed an identical hepatitis. Finally, primary rat hepatocytes in culture also showed apoptosis when cultured in the presence of rIL-4. IL-4-dependent he patitis was associated with increases in the intrahepatic levels of IFN-gam ma, TNF-alpha, and Fas ligand. Administration of AdmIL-4 to IFN-gamma, TNF- alpha receptor type 1, or TNF-alpha receptor type 11 knockout mice also res ulted in lethal hepatitis, whereas a moderate protection was observed in Fa s-deficient lpr mice. IL-4-dependent hepatocyte apoptosis could be abolishe d by treatment with caspase inhibitory peptides. Our results thus demonstra te that IL-4 causes hepatocyte apoptosis, which is only partially dependent on the activation of Apo-l-Fas signaling and is largely independent of any immune cells in the liver.