DIFFERENTIAL DYSREGULATION OF NITRIC-OXIDE PRODUCTION IN MACROPHAGES WITH TARGETED DISRUPTIONS IN IFN REGULATORY FACTOR-1 AND FACTOR-2 GENES

Recent studies have reported that IFN regulatory factor-1 (IRF-1) regu lates nitric oxide (NO.) production in murine macrophages (M phi). Sin ce IRF-2 recognizes the same consensus sequence as IRF-1, we postulate d that IRF-2 may also regulate NO.. Therefore, the ability of M phi fr om IRF-2 homozygous (IRF-2(-/-)) and heterozygous (IRF-2(+/-)) knockou t mice to produce NO. following LPS and/or IFN-gamma stimulation was c ompared 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- pro duction from IRF-2(-/-) M phi to similar to 50% of IRF-2(+/-) and C57B L/6 levels, Unexpectedly, IRF-2(-/-), IRF-2(+/-), and C57BL/6 M phi pr oduced comparable levels of inducible NO. synthase mRNA in response to treatment with LPS and IFN-gamma, IRF-1(-/-) M phi produced barely de tectable NO2- and low, but detectable, inducible NO. synthase mRNA in response to IFN-gamma and LPS. These results indicate that IRF-1 and I RF-2 differ in their mechanism of NO. regulation and that IRF-2 regula tes inducible NO. synthase post-transcriptionally.