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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / genetics*
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Adjuvants, Immunologic / physiology
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Allergens / administration & dosage
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Allergens / immunology*
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Animals
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Carrier Proteins / genetics*
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Carrier Proteins / physiology
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Cytokines / biosynthesis*
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DNA-Binding Proteins / biosynthesis
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Down-Regulation / immunology
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GATA3 Transcription Factor
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Immunoglobulin E / biosynthesis
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Immunoglobulin E / blood
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Immunoglobulin G / biosynthesis
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Immunoglobulin G / blood
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Interleukin-4 / biosynthesis
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Interphase / genetics
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Interphase / immunology
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Intracellular Signaling Peptides and Proteins*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Protein Binding / genetics
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Protein Binding / immunology
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Protein Isoforms / genetics
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Protein Isoforms / physiology
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Respiratory Hypersensitivity / genetics
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Respiratory Hypersensitivity / immunology*
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Respiratory Hypersensitivity / pathology*
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Th2 Cells / immunology*
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Th2 Cells / metabolism*
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Trans-Activators / biosynthesis
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Transcription Factor AP-1 / metabolism
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Up-Regulation / immunology
Substances
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Adjuvants, Immunologic
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Allergens
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins
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Cflar protein, mouse
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Cytokines
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DNA-Binding Proteins
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Immunoglobulin G
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Protein Isoforms
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Trans-Activators
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Transcription Factor AP-1
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Interleukin-4
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Immunoglobulin E
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Interferon-gamma
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Ovalbumin