Differential dysregulation of nitric oxide production in macrophages with targeted disruptions in IFN regulatory factor-1 and -2 genes.
Recent studies have reported that IFN regulatory factor-1 (IRF-1) regulates nitric oxide (NO.) production in murine macrophages (M phi). Since IRF-2 recognizes the same consensus sequence as IRF-1, we postulated that IRF-2 may also regulate NO.. Therefore, the ability of M phi from INF-2 homozygous (IRF-2-/-) and heterozygous (IRF-2+/-) knockout mice to produce NO. following LPS and/or IFN-gamma stimulation was compared with the responses of IRF-1-/-, IRF-1+/-, and C57BL/6+/+ M phi. IRF-2-/- M phi produced less LPS-induced NO2- than IRF-2+/- or C57BL/6 M phi. LPS and IFN-gamma synergized to increase NO2- production from IRF-2-/- M phi to approximately 50% of IRF-2+/- and C57BL/6 levels. Unexpectedly, IRF-2-/-, IRF-2+/- and C57BL/6 M phi produced comparable levels of inducible NO synthase mRNA in response to treatment with LPS and IFN-gamma. IRF-1-/- M phi produced barely detectable NO2- and low, but detectable, inducible NO. synthase mRNA in response to IFN-gamma and LPS. These results indicate that IRF-1 and IRF-2 differ in their mechanism of NO. regulation and that IRF-2 regulates inducible NO. synthase post-transcriptionally.
Salkowski
C A
CA
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Barber
S A
SA
Detore
G R
GR
Vogel
S N
SN
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology*; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins; D014157:Transcription Factors / Q000502:physiology
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse; D010750:Phosphoproteins; D012097:Repressor Proteins; D014157:Transcription Factors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase