Nramp1-functionality increases iNOS expression via repression of IL-10 formation

Eur J Immunol. 2008 Nov;38(11):3060-7. doi: 10.1002/eji.200838449.


In mice, resistance to certain intracellular microbes depends on the expression of a late phagosomal protein termed natural-resistance associated macrophage protein 1 (Nramp1, Slc11a1). Nramp1-functionality is associated with alterations of cellular iron homeostasis and a sustained pro-inflammatory immune response, including the formation of the antimicrobial effector molecule NO. To investigate the underlying mechanism we used RAW-264.7 murine macrophage cells stably transfected with a functional Nramp1 allele (RAW-37) or Nramp1 non-functional controls (RAW-21). We found that the production of and signalling by the anti-inflammatory cytokine IL-10 was significantly enhanced in macrophages lacking functional Nramp1. Upon infection of macrophages with Salmonella typhimurium pathogen survival was significantly better in RAW-21 than in RAW-37, which inversely correlated to NO and TNF-alpha formation. Addition of a neutralising anti-IL-10 antibody to RAW-21 cells led to a significantly reduced survival of S. typhimurium within these cells and enhanced formation of NO and TNF-alpha reaching levels comparable to that observed in cells bearing functional Nramp1. Oppositely, supplementation of iron to RAW-21 cells further increased IL-10 formation.Thus, Nramp1 mediates effective host defence in part via suppression of excessive IL-10 production which may relate to Nramp1-mediated reduction of cellular iron pools, thus strengthening antimicrobial effector mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cation Transport Proteins / physiology*
  • Cells, Cultured
  • Interleukin-10 / antagonists & inhibitors
  • Interleukin-10 / biosynthesis*
  • Mice
  • Mice, Inbred BALB C
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type II / biosynthesis*
  • STAT3 Transcription Factor / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Cation Transport Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Tumor Necrosis Factor-alpha
  • natural resistance-associated macrophage protein 1
  • Interleukin-10
  • Nitric Oxide
  • Nitric Oxide Synthase Type II