Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair

Xiaoling Jin, Teresa A. Zimmers, Eduardo A. Perez, Robert H. Pierce, Zongxiu Zhang, Leonidas G. Koniaris

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


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 proapoptotic 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.

Original languageEnglish (US)
Pages (from-to)474-484
Number of pages11
Issue number3
StatePublished - Mar 2006

ASJC Scopus subject areas

  • Hepatology


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