Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair.
Interleukin-6 (IL-6) is an important mediator of liver regeneration and repair that is also elevated in chronic liver diseases, including fatty liver of obesity and cirrhosis. IL-6 has been reported both to delay and accelerate liver regeneration. We examined the effects on liver injury and regeneration of a continuous administration of exogenous IL-6 to mice by injection of an IL-6-expressing CHO-cell line in athymic nude mice and by osmotic mini-pump delivery of recombinant murine IL-6. Short-term IL-6 administration (1-2 days) accelerated early recovery of liver mass, whereas more long-term administration (5-7 days) markedly impaired liver regeneration. Similarly, short-term IL-6 treatment increased hepatic resistance to the lethal effects of the Fas agonist Jo-2, but on more prolonged IL-6 exposure the Jo-2 resistance vanished. IL-6 administration initially induced expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL, correlating with protection against Fas-mediated cell death. More prolonged IL-6 administration, however, resulted in marked induction of the pro-apoptotic protein Bax. This result coincided with increased activation of the type II or intrinsic, mitochondrial path to cell death, manifested by increased caspase-9 activation and increased cytochrome c release after Jo-2 exposure. These data demonstrate that IL-6 can function acutely to improve hepatic regeneration and repair, but that more chronic exposure not only abolishes the protective effects of IL-6, but actually sensitizes the liver to injury and death. In conclusion, elevated IL-6 in certain chronic liver diseases contributes to an increased likelihood of liver failure after injury.
Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
Xiaoling
X
Jin
Teresa A
TA
Zimmers
Eduardo A
EA
Perez
Robert H
RH
Pierce
Zongxiu
Z
Zhang
Leonidas G
LG
Koniaris
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D053453:Caspase 9; D020169:Caspases; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006498:Hepatectomy / Q000009:adverse effects; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D008115:Liver Regeneration / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008930:Mitochondria, Liver; D011994:Recombinant Proteins; D014945:Wound Healing / Q000187:drug effects; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019014:fas Receptor
D015850:Interleukin-6; D011994:Recombinant Proteins; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019014:fas Receptor; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases