Enhanced expression of Fas-associated death domain-like IL-1-converting enzyme (FLICE)-inhibitory protein induces resistance to Fas-mediated apoptosis in activated mast cells.
Mast cells play a critical role in host immune responses and are implicated in the pathogenesis of allergic inflammation. Though mouse mast cell line MC/9 expresses cell surface Fas Ag and is sensitive to Fas-induced apoptosis, activated MC/9 cells are resistant to Fas-induced cell death by cross-linking of FcepsilonRI or FcgammaR. Fas-associated death domain-like IL-1-converting enzyme (FLICE)-inhibitory protein (FLIP), a caspase-8 inhibitor that lacks the cysteine domain, is one of the negative regulators of receptor-mediated apoptosis. In this report, we show that activation of mast cells by cross-linking of FcepsilonRI or FcgammaR can induce enhanced expression of FLIP and consequently a resistance to Fas-induced apoptosis, although the expression level of Fas Ag is not changed. Addition of antisense oligonucleotide for FLIP prevents resistance to Fas-induced apoptosis of activated mast cells, suggesting that endogenous FLIP inhibits Fas-mediated apoptosis in activated mast cells. Thus, the enhanced expression of FLIP in activated mast cells contributes to the resistance to Fas-induced apoptosis, which may result in the development and prolongation of allergic inflammation.
Yoshikawa
H
H
Department of Parasitology and Immunology, Yamanashi Medical University, Yamanashi, Japan.
Nakajima
Y
Y
Tasaka
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D007113:Immunity, Innate; D007425:Intracellular Membranes / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008564:Membrane Potentials / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; C494812:Bcl2l1 protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017455:Receptors, IgE; D017452:Receptors, IgG; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1