Bruton's Tyrosine Kinase Deficiency in Macrophages Inhibits Nitric Oxide Generation Leading to Enhancement of IL-12 Induction

• Published in: The Journal of immunology (1950) 1999-08, Vol.163 (4), p.1786-1792
• Main Authors: Mukhopadhyay, Sangita, George, Anna, Bal, Vineeta, Ravindran, Balachandran, Rath, Satyajit
• Format: Article
• Language: English
• Subjects: Animals; Chickens; Conalbumin - administration & dosage; Conalbumin - immunology; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Enzyme Inhibitors - pharmacology; Guanidines - pharmacology; Immunologic Deficiency Syndromes - enzymology; Immunologic Deficiency Syndromes - genetics; Interferon Regulatory Factor-1; Interleukin-12 - antagonists & inhibitors; Interleukin-12 - biosynthesis; Lymphocyte Activation - genetics; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred CBA; Mice, Mutant Strains; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Nitric Oxide - pharmacology; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase - deficiency; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type II; Phosphoproteins - biosynthesis; Phosphoproteins - genetics; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics; STAT1 Transcription Factor; T-Lymphocytes - immunology; Trans-Activators - biosynthesis; Trans-Activators - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.4.1786

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.