title: Cellular FLIP long form-transgenic mice manifest a Th2 cytokine bias and enhanced allergic airway inflammation.
abstract: Cellular FLIP long form (c-FLIP(L)) is a caspase-defective homologue of caspase-8 that blocks apoptosis by death receptors. The expression of c-FLIP(L) in T cells can also augment extracellular signal-regulated kinase phosphorylation after TCR ligation via the association of c-FLIP(L) with Raf-1. This contributes to the hyperproliferative capacity of T cells from c-FLIP(L)-transgenic mice. In this study we show that activated CD4(+) T cells from c-FLIP(L)-transgenic mice produce increased amounts of Th2 cytokines and decreased amounts of Th1 cytokines. This correlates with increased serum concentrations of the Th2-dependent IgG1 and IgE. The Th2 bias of c-FLIP(L)-transgenic CD4(+) T cells parallels impaired NF-kappa B activity and increased levels of GATA-3, which contribute, respectively, to decreased IFN-gamma and increased Th2 cytokines. The Th2 bias of c-FLIP(L)-transgenic mice extends to an enhanced sensitivity to OVA-induced asthma. Taken together, these results show that c-FLIP(L) can influence cytokine gene expression to promote Th2-driven allergic reaction, in addition to its traditional role of blocking caspase activation induced by death receptors.
authors.affiliation: Immunobiology Program, Department of Medicine, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Wu
authors.forename: Lisa
authors.initials: L
authors.lastname: Rinaldi
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fortner
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Russell
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Charles
authors.initials: C
authors.lastname: Irvin
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics* / Q000502:physiology; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D050990:GATA3 Transcription Factor; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000097:blood; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007399:Interphase / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D015534:Trans-Activators / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000485:Allergens; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D020033:Protein Isoforms; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin