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

Abstract

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-γ 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.