Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice.
Interleukin-6 null (IL-6-/-) mice have impaired liver regeneration and increased liver necrosis following partial hepatectomy that is corrected with IL-6 treatment. Following acute carbon tetrachloride (CCl(4)) treatment, we found that IL-6-/- mice developed increased hepatocellular injury and defective regeneration with significant blunting of signal transducer-and-activator of transcription protein 3 (STAT3) and nuclear factor-kappaB (NF-kappaB) activation and reduced hepatocyte DNA synthetic and mitotic responses. After CCl(4) treatment, unlike partial hepatectomy, increased hepatocyte apoptosis was noted in IL-6-/- livers. Pretreatment with IL-6 before CCl(4) reduced acute CCl(4) injury and apoptosis and accelerated regeneration in both IL-6+/+ and -/- livers. Repetitive doses of CCl(4) in the presence or absence of phenobarbital resulted in increased injury and fibrosis in IL-6 -/- compared with +/+ livers. After acute and chronic injury, IL-6-/- livers showed the protracted presence of alpha-smooth muscle actin associated with activated stellate cells, indicating a disturbed response in wound healing that progressed to fibrosis. These data provide evidence for an important role for IL-6 in reducing CCl(4)-induced acute and chronic liver injury and fibrosis.
Kovalovich
K
K
Department of Genetics, University of Pennsylvania Medical School, Philadelphia, PA 19104, USA.
DeAngelis
R A
RA
Li
W
W
Furth
E E
EE
Ciliberto
G
G
Taub
R
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000172:deficiency* / Q000502:physiology; D007700:Kinetics; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D016328:NF-kappa B / Q000378:metabolism; D010634:Phenobarbital / Q000008:administration & dosage; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D000199:Actins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D004247:DNA; D002251:Carbon Tetrachloride; D010634:Phenobarbital