Interleukin 1beta protects mice from Fas-mediated hepatocyte apoptosis and death.
OBJECTIVE
Fas-mediated apoptosis is one of the major death processes of hepatocytes in liver diseases. The aim of this study was to determine whether interleukin (IL)-1beta regulates the Fas-mediated apoptotic process of differentiated hepatocytes in vivo.


METHODS
IL-1beta was injected into Balb/cA mice 5 hours before lethal challenge with agonistic anti-Fas administration. Survival and hepatocyte apoptotic process of these mice were examined.


RESULTS
IL-1beta pretreatment prolonged animal survival in a dose-dependent manner, and 500 ng of IL-1beta completely protected mice from lethality. Both serum alanine aminotransferase value and hepatic DNA fragmentation were significantly suppressed by IL-1beta pretreatment. IL-1beta affected neither hepatic distribution of anti-Fas antibody nor Fas expression levels on hepatocytes but significantly suppressed Fas-induced activation of hepatic caspase 3-like protease. Suppression of Fas-induced activation of the caspase by IL-1beta was diminished by coadministration with D-galactosamine and reversed by coinjection with an excess amount of uridine.


CONCLUSIONS
These results suggest that IL-1beta suppresses Fas-mediated hepatocyte apoptosis by inducing molecule(s) that suppress the apoptosis control machinery upstream of caspase 3. This observation raises the possibility that IL-1beta acts as a negative regulator of Fas-mediated hepatocyte apoptosis during liver injury.
Takehara
T
T
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.
Hayashi
N
N
Tatsumi
T
T
Kanto
T
T
Mita
E
E
Sasaki
Y
Y
Kasahara
A
A
Hori
M
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D053938:DNA Fragmentation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007375:Interleukin-1 / Q000494:pharmacology* / Q000502:physiology; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019014:fas Receptor / Q000378:metabolism
D004792:Enzyme Precursors; D007375:Interleukin-1; D019014:fas Receptor; D000410:Alanine Transaminase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases