The Fas-FasL death receptor and PI3K pathways independently regulate monocyte homeostasis.
Peripheral blood-derived monocytes spontaneously undergo apoptosis mediated by Fas-Fas ligand (FasL) interactions. Activation of monocytes by LPS or TNF-alpha prevents spontaneous monocyte apoptosis through an unknown mechanism. Here, we demonstrate that LPS and TNF-alpha up-regulate Flip and suppress spontaneous Fas-FasL mediated monocyte apoptosis and caspase 8 and 3 activation. Flip was responsible for this protection, since inhibition of Flip by antisense oligonucleotides in the presence of LPS or TNF-alpha restored monocyte sensitivity to spontaneous apoptosis. We also investigated whether the PI3K pathway contributes to the suppression of spontaneous monocyte apoptosis mediated by LPS and TNF-alpha. Monocytes treated with a reversible PI3K inhibitor (LY294002) displayed enhanced apoptosis, while LPS and TNF-alpha partially protected against apoptosis mediated by LY294002. However, direct suppression of Fas-FasL interactions by addition of neutralizing anti-FasL antibody did not further suppress LY294002-induced apoptosis in the presence of LPS or TNF-alpha. Collectively, these data demonstrate that LPS or TNF-alpha protect monocytes from death receptor-mediated apoptosis through the up-regulation of Flip, but not apoptosis initiated by inhibition of the PI3K pathway.
Perlman
H
H
Northwestern University Medical School and the Veterans Administration Chicago Healthcare System, Lakeside Division, Division of Rheumatology, Chicago, IL 60611, USA.
Pagliari
L J
LJ
Nguyen
N
N
Bradley
K
K
Liu
H
H
Pope
R M
RM
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D006706:Homeostasis / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism*
D000906:Antibodies; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D020169:Caspases; D002867:Chromones; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one