Nramp1-functionality increases iNOS expression via repression of IL-10 formation.
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.
Fritsche
Gernot
G
Department of Internal Medicine, Innsbruck Medical University, Austria.
Nairz
Manfred
M
Werner
Ernst R
ER
Barton
Howard C
HC
Weiss
Günter
G
D000818:Animals; D027682:Cation Transport Proteins / Q000502:physiology*; D002478:Cells, Cultured; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D016753:Interleukin-10; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000099173:Natural Resistance-associated Macrophage Protein 1; C494087:Stat3 protein, mouse