Bruton's tyrosine kinase deficiency in macrophages inhibits nitric oxide generation leading to enhancement of IL-12 induction.
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.
Mukhopadhyay
S
S
National Institute of Immunology, New Delhi, India.
George
A
A
Bal
V
V
Ravindran
B
B
Rath
S
S
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002645:Chickens; D003207:Conalbumin / Q000008:administration & dosage / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics; D050856:Interferon Regulatory Factor-1; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics*; D050794:STAT1 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006146:Guanidines; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D003207:Conalbumin; D018664:Interleukin-12; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; C004479:pimagedine