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Prepublished online as a Blood First Edition Paper on October 10, 2002; DOI 10.1182/blood-2002-06-1720.
Submitted June 11, 2002
Accepted September 16, 2002
Stem Cell Factor increases the expression of FLIP which inhibits IFN -induced apoptosis in human erythroid progenitor cells
Ik-Joo Chung, Chunhua Dai, and Sanford B Krantz*
Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA; Medical Service, VA Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
* Corresponding author; email: Sanford.Krantz{at}med.va.gov.
Interferon  (IFN) acts on human erythroid colony-forming cells (ECFC) to up-regulate Fas, without a demonstrable change of Fas ligand (FasL) or 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 ECFC when both factors were present in the cultures. However, the mechanism by which SCF prevents IFN-induced apoptosis in ECFC is unclear. In this study we used highly purified human ECFC to investigate the mechanism of the effect of SCF on IFN-induced apoptosis. Since the binding of FasL to Fas is the first step of the apoptosis cascade, and IFN strongly up-regulates Fas expression, we added FasL (50ng/mL) to the cultures with IFN to accentuate the IFN-induced activation of caspase-8 and caspase-3 plus subsequent apoptosis. SCF (100ng/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 TUNEL assay. SCF did not decrease the surface expression of Fas on the ECFC. 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 act as a dominant negative caspase-8. SCF increased FLIP mRNA and protein expression, concomitant with reduced apoptosis, while 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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