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J Biol Chem, Vol. 274, Issue 33, 23013-23019, August 13, 1999
From the Institute of Molecular Medicine and the
The multifunctional cytokine interleukin-6 (IL-6)
regulates growth and differentiation of many cell types and induces
production of acute-phase proteins in hepatocytes. Here we report that
IL-6 protects hepatoma cells from apoptosis induced by transforming growth factor-
Interleukin-6 Inhibits Transforming Growth Factor-
-induced
Apoptosis through the Phosphatidylinositol 3-Kinase/Akt and Signal
Transducers and Activators of Transcription 3 Pathways
,
Institute of Toxicology, College of Medicine, National
Taiwan University, Taipei, Taiwan
(TGF-), a well known apoptotic inducer in liver cells. Addition of IL-6 blocked TGF--induced activation of caspase-3 while showing no effect on the induction of plasminogen activator inhibitor-1 and p15INK4B genes, indicating that IL-6 interferes
with only a subset of TGF- activities. To further elucidate the
mechanism of this anti-apoptotic effect of IL-6, we investigated which
signaling pathway transduced by IL-6 is responsible for this effect.
IL-6 stimulation of hepatoma cells induced a rapid tyrosine
phosphorylation of the p85 subunit of phosphatidylinositol 3-kinase (PI
3-kinase) and its kinase activity followed by the activation of Akt.
Inhibition of PI 3-kinase by wortmannin or LY294002 abolished the
protection of IL-6 against TGF--induced apoptosis. A
dominant-negative Akt also abrogated this anti-apoptotic effect.
Dominant-negative inhibition of STAT3, however, only weakly attenuated
the IL-6-induced protection. Finally, inhibition of both STAT3 and PI
3-kinase by treating cells overexpressing the dominant-negative STAT3
with LY294002 completely blocked IL-6-induced survival signal. Thus,
concomitant activation of the PI 3-kinase/Akt and the STAT3 pathways
mediates the anti-apoptotic effect of IL-6 against TGF-, with the
former likely playing a major role in this anti-apoptosis.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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