Abstract
Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) can interact with various members of the TNF receptor family. Previously, we reported that TRAF2-deficient mice die prematurely and have elevated serum TNF levels. In this study, we demonstrate that TRAF2-deficient macrophages produce increased amounts of nitric oxide (NO) and TNF in response to TNF stimulation. Furthermore, we could enhance the survival of TRAF2-deficient mice by eliminating either TNF or TNFR1. Using these double-knockout mice, we show that in the absence of TRAF2, the T helper-dependent antibody response, CD40-mediated proliferation, and NF-kappaB activation are defective. These data demonstrate two important roles of TRAF2, one as a negative regulator of certain TNFR1 signals and the other as a positive mediator of CD40 signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / metabolism*
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CD40 Antigens / metabolism*
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Cell Division
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Cells, Cultured
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Female
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Immunoglobulin Class Switching
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Immunoglobulin Isotypes
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Interleukin-12 / biosynthesis
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Macrophages, Peritoneal / cytology
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Macrophages, Peritoneal / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B / metabolism
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Phenotype
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Proteins / genetics
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Proteins / physiology*
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Signal Transduction*
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Spleen / cytology
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha / biosynthesis
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Vesicular stomatitis Indiana virus
Substances
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Antigens, CD
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CD40 Antigens
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Immunoglobulin Isotypes
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NF-kappa B
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Proteins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha
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Interleukin-12
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Nitric Oxide
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse