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 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.
Guillot
C
C
Institut National de la Santé et de la Recherche Médicale, Unité 437, Nantes, France.
Coathalem
H
H
Chetritt
J
J
David
A
A
Lowenstein
P
P
Gilbert
E
E
Tesson
L
L
van Rooijen
N
N
Cuturi
M C
MC
Soulillou
J P
JP
Anegon
I
I
D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000590:Amino Acid Chloromethyl Ketones / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D061945:Caspase Inhibitors; D002465:Cell Movement / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D053222:Fas Ligand Protein; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006524:Hepatitis, Viral, Animal / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology*; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D007728:Kupffer Cells / Q000276:immunology / Q000821:virology; D007962:Leukocytes / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D051381:Rats; D011923:Rats, Nude; D017208:Rats, Wistar; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma