Abstract
We show that macrophages of X-linked immunodeficient mice with a mutant nonfunctional Bruton's tyrosine kinase produce less NO than wild-type macrophages in response to a variety of stimuli. Induction of the inducible NO synthase (iNOS) protein, the transcription factor IFN regulatory factor-1 involved in iNOS expression, and the transcription factor STAT-1 involved in regulating IFN regulatory factor-1 induction are all poorer in X-linked immunodeficient than in wild-type macrophages. On the other hand, induction of IL-12 is higher in X-linked immunodeficient than in wild-type macrophages. Macrophage IL-12 induction is enhanced by iNOS inhibitors such as aminoguanidine and thiocitrulline and is inhibited by NO generation via sodium nitroprusside. There is relative enhancement of IFN-gamma production by immune T cells from mice immunized under aminoguanidine cover. Our data thus suggest that Bruton's tyrosine kinase participates in signaling for iNOS induction via IFN regulatory factor-1 in macrophages and that NO is an inhibitor of IL-12 induction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Chickens
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Conalbumin / administration & dosage
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Conalbumin / immunology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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Enzyme Inhibitors / pharmacology
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Guanidines / pharmacology
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Immunologic Deficiency Syndromes / enzymology
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Immunologic Deficiency Syndromes / genetics
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Interferon Regulatory Factor-1
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / biosynthesis*
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Lymphocyte Activation / genetics
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Macrophages, Peritoneal / enzymology*
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred CBA
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Mice, Mutant Strains
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Nitric Oxide / antagonists & inhibitors*
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Nitric Oxide / biosynthesis*
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Nitric Oxide / pharmacology
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / deficiency
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Phosphoproteins / biosynthesis
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Phosphoproteins / genetics
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Protein-Tyrosine Kinases / deficiency*
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Protein-Tyrosine Kinases / genetics*
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STAT1 Transcription Factor
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T-Lymphocytes / immunology
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Trans-Activators / biosynthesis
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Trans-Activators / genetics
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Guanidines
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Interferon Regulatory Factor-1
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Irf1 protein, mouse
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Phosphoproteins
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STAT1 Transcription Factor
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Stat1 protein, mouse
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Trans-Activators
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Conalbumin
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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
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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Btk protein, mouse
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pimagedine