The NF-kappa B signaling pathway is not required for Fas ligand gene induction but mediates protection from activation-induced cell death.
Stimulation of T cells by antigens or mitogens triggers multiple signaling pathways leading to activation of genes encoding interleukin-2 and other growth-regulatory cytokines. The same stimuli also activate the gene encoding an apoptosis-inducing molecule, Fas ligand (FasL), which contributes to activation-induced cell death. It has been proposed that the signaling pathways involved in cytokine gene induction also contribute to activation-induced FasL expression; however, genetic evidence for this proposal is lacking. In the present study, the role of the NF-kappaB signaling pathway in FasL gene expression was examined using a mutant T cell line deficient in an essential NF-kappaB signaling component, IkappaB kinase gamma. These mutant cells have a blockade in signal-induced activation of NF-kappaB but remained normal in the activation of NF-AT and AP-1 transcription factors. Interestingly, the NF-kappaB signaling defect has no effect on mitogen-stimulated FasL gene expression, although it completely blocks the interleukin-2 gene induction. We further demonstrate that NF-kappaB activation is required for protecting T cells from apoptosis induction by mitogens and an agonistic anti-Fas antibody. These genetic results suggest that the NF-kappaB signaling pathway is not required for activation-induced FasL expression but rather mediates cell growth and protection from activation-induced cell death.
Rivera-Walsh
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I
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey Medical Center, 17033, USA.
Cvijic
M E
ME
Xiao
G
G
Sun
S C
SC
D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase; D015151:Immunoblotting; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D016296:Mutagenesis; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection
D017304:Annexin A5; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D008934:Mitogens; D016328:NF-kappa B; D012333:RNA, Messenger; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human