Regulation of type 2 nitric oxide synthase by type 1 interferons in macrophages infected withLeishmania major (original) (raw)

2000, European Journal of Immunology

We recently reported that the infection of macrophages with Leishmania major led to the release of type 1 interferons (IFN- § / g ). Moreover, at day 1 of infection of mice with L. major, IFN- § / g was required for the expression of type 2 (inducible) NO synthase (NOS2 or iNOS) which, however, was restricted to a few macrophages in the dermis. Here, we further characterized the regulation of NOS2 by IFN- § / g . Macrophages that were either simultaneously or sequentially exposed to L. major promastigotes and IFN- § / g expressed NOS2 and antileishmanial activity. In contrast, when high amounts of IFN- § / g were used or when IFN- § / g was added to the macrophages 2 h prior to the parasites, almost no induction of NOS2 was observed. After pretreatment with IFN- § / g , tyrosine phosphorylation and nuclear DNA binding of Stat1 § , the degradation of the NF-‹ B inhibitor (I ‹ B § and g ), and the nuclear translocation of NF-‹ B were strongly impaired compared with macrophages exposed to IFN- § / g and L. major simultaneously. Thus, IFN- § / g exerts agonistic or antagonistic effects on the expression of NOS2 in macrophages infected with a microbial pathogen, depending on the sequence of the stimuli and the amount of IFN- § / g added. The limited number of NOS2positive macrophages at day 1 of infection in vivo might result from a blockage of noninfected macrophages by IFN- § / g that is released by neighboring infected cells. Abbreviations: mSDM: Modified Schneider's drosophila medium NO: Nitric oxide NOS2/iNOS: Type 2 (inducible) NO synthase Stat1 > : Signal transducer and activator of transcription 1 § Stat1 > -PY: Tyrosine-phosphorylated Stat1 § Eur.

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