Regulation of type 2 nitric oxide synthase by type 1 interferons in macrophages infected with Leishmania major

Thomas Lehner, Elaine Mitchell, Lesley Bergmeier, Mahavir Singh, Ralf Spallek, Martin Cranage, Graham Hall, Michael Dennis, Francois Villinger, Yufei Wang

Research output: Contribution to journalArticlepeer-review

45 Citations (Scopus)

Abstract

We recently reported that the infection of macrophages with Leishmania major led to the release of type 1 interferons (IFN-α/β). Moreover, at day 1 of infection of mice with L. major, IFN-α/β 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-α/β. Macrophages that were either simultaneously or sequentially exposed to L. major promastigotes and IFN-α/β expressed NOS2 and anti-leishmanial activity. In contrast, when high amounts of IFN-α/β were used or when IFN-α/β was added to the macrophages 2 h prior to the parasites, almost no induction of NOS2 was observed. After pretreatment with IFN-α/β, tyrosine phosphorylation and nuclear DNA binding of Stat 1 α, the degradation of the NF-κB inhibitor (IκBα and β), and the nuclear translocation of NF-κB were strongly impaired compared with macrophages exposed to IFN-α/β and L. major simultaneously. Thus, IFN-α/β 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-α/β added. The limited number of NOS2-positive macrophages at day 1 of infection in vivo might result from a blockage of non-infected macrophages by IFN-α/β that is released by neighboring infected cells.

Original languageEnglish
Pages (from-to)2257-2267
Number of pages11
JournalEuropean Journal of Immunology
Volume30
Issue number8
DOIs
Publication statusPublished - 2000

Keywords

  • IFN-α/β
  • Macrophage
  • Type 2 nitric oxide synthase

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