Mature dendritic cells are protected from Fas/CD95-mediated apoptosis by upregulation of Bcl-X(L).
The clinical use of dendritic cells (DC) as tumor vaccines is very much dependent on their survival potential. Members of the tumor necrosis factor (TNF) receptor superfamily and their ligands are involved in the regulation of cell death. Fas (CD95) is a representative protein that promotes apoptosis. The Bcl-2 family of proteins functions as an integrator of diverse pro- and anti-apoptotic signals. It has been found that DC maturation facilitates their survival, and thus has an anti-apoptotic function. However, little is known about the underlying mechanisms. We investigated the effects of TNF-alpha and lipopolysaccharide (LPS) on the expression of apoptotic molecules during differentiation and maturation of DC under serum-free conditions, and correlated this to the sensitivity to apoptosis by the Fas-mediated pathway. Indeed, DC activation effectively inhibited DC apoptosis, which was predominantly accompanied by the upregulation of Bcl-X(L) and to a lesser extent Bcl-2, while Bax and FLICE inhibitory protein (FLIP) remained unchanged. In contrast, in the presence of serum FLIP was also upregulated. We conclude that under serum-free conditions, Bcl-X(L) rather than FLIP plays the main role in protection against DC apoptosis.
Lundqvist
Andreas
A
Cancer Center Karolinska, Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Radiumhemmet, Karolinska Institute, 171 77 Stockholm, Sweden.
Nagata
Takako
T
Kiessling
Rolf
R
Pisa
Pavel
P
D017209:Apoptosis; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism*; D002454:Cell Differentiation; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation; D051020:bcl-X Protein; D019014:fas Receptor / Q000096:biosynthesis* / Q000378:metabolism
C494811:BCL2L1 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019014:fas Receptor; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor