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-Induced Sphingosine 1-Phosphate Inhibits Apoptosis Through a Phosphatidylinositol 3-Kinase/Akt Pathway in Human Hepatocytes1
*
First Department of Internal Medicine and
Department of Biochemistry, Gifu University School of Medicine, Gifu, Japan;
Departments of Medicine, Biochemistry, and Biophysics, University of North Carolina, Chapel Hill, NC 27599; and
Gifu International Institute of Biotechnology, Institute of Applied Biochemistry, Gifu, Japan
Human hepatocytes usually are resistant to TNF-
cytotoxicity. In
mouse or rat hepatocytes, repression of NF-
B activation is
sufficient to induce TNF--mediated apoptosis. However, in both Huh-7
human hepatoma cells and Hc human normal hepatocytes, when infected
with an adenovirus expressing a mutated form of IB (Ad5IB),
which almost completely blocks NF-B activation, >80% of the cells
survived 24 h after TNF- stimulation. Here, we report that
TNF- activates other antiapoptotic factors, such as sphingosine
kinase (SphK), phosphatidylinositol 3-kinase (PI3K), and Akt kinase.
Pretreatment of cells with N,N-dimethylsphingosine
(DMS), an inhibitor of SphK, or LY 294002, an inhibitor of PI3K that
acts upstream of Akt, increased the number of apoptotic cells induced
by TNF- in Ad5IB-infected Huh-7 and Hc cells. TNF--induced
activations of PI3K and Akt were inhibited by DMS. In contrast,
exogenous sphingosine 1-phosphate, a product of SphK, was found to
activate Akt and partially rescued the cells from TNF--induced
apoptosis. Although Akt has been reported to activate NF-B, DMS and
LY 294002 failed to prevent TNF--induced NF-B activation,
suggesting that the antiapoptotic effects of SphK and Akt are
independent of NF-B. Furthermore, apoptosis mediated by Fas ligand
(FasL) involving Akt activation also was potentiated by DMS
pretreatment in Hc cells. Sphingosine 1-phosphate administration
partially protected cells from FasL-mediated apoptosis. These results
indicate that not only NF-B but also SphK and PI3K/Akt are involved
in the signaling pathway(s) for protection of human hepatocytes from
the apoptotic action of TNF- and probably FasL.
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