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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-06-1720.
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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1324-1328
HEMATOPOIESIS
Stem cell factor increases the expression of FLIP that inhibits
IFN -induced apoptosis in human erythroid progenitor cells
Ik-Joo Chung,
Chunhua Dai, and
Sanford B. Krantz
From the Department of Veterans Affairs Medical
Service, Department of Medicine, Division of Hematology/Oncology; and
the Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville,
TN.
Interferon  (IFN) acts on human erythroid colony-forming
cells (ECFCs) to up-regulate Fas, without a demonstrable change of Fas
ligand (FasL) or Fas-associated DD-containing protein (FADD) expression
and activates caspase-8 plus caspase-3, which produce apoptosis. Our
previous data showed that stem cell factor (SCF) reduced the inhibitory
effect of IFN on human ECFCs when both factors were present in the
cultures. However, the mechanism by which SCF prevents IFN-induced
apoptosis in ECFCs is unclear. In this study we used highly purified
human ECFCs to investigate the mechanism of the effect of SCF on
IFN-induced apoptosis. Because the binding of FasL to Fas is the
first step of the apoptosis cascade and IFN strongly up-regulates
Fas expression, we added FasL (50 ng/mL) to the cultures with IFN to
accentuate the IFN-induced activation of caspase-8 and caspase-3
plus subsequent apoptosis. SCF (100 ng/mL) clearly inhibited the
activation of caspase-8 and caspase-3 induced by IFN and/or FasL,
and it also reduced apoptosis as measured by the terminal dUTP nick-end
labeling (TUNEL) assay. SCF did not decrease the surface expression of
Fas on the ECFCs. FADD-like interleukin 1  (IL-1)-converting
enzyme (FLICE)-inhibitory protein (FLIP) has been reported to interact
with FADD and/or caspase-8 at the death-inducing signaling complex
(DISC) level following Fas stimulation and acts as a dominant-negative
caspase-8. SCF increased FLIP mRNA and protein expression, concomitant
with reduced apoptosis, whereas IFN and/or FasL did not change FLIP expression. Reduction of FLIP expression with antisense
oligonucleotides decreased the capacity of SCF to inhibit
IFN-induced apoptosis, demonstrating a definite role for FLIP in the
SCF-induced protection of ECFCs from IFN-initiated apoptosis.
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