These authors contributed equally to this work.
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Immunity to infection
Nramp1-functionality increases iNOS expression via repression of IL-10 formation
Article first published online: 7 NOV 2008
DOI: 10.1002/eji.200838449
Copyright © 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Additional Information
How to Cite
Fritsche, G., Nairz, M., Werner, E. R., Barton, H. C. and Weiss, G. (2008), Nramp1-functionality increases iNOS expression via repression of IL-10 formation. Eur. J. Immunol., 38: 3060–3067. doi: 10.1002/eji.200838449
Publication History
- Issue published online: 7 NOV 2008
- Article first published online: 7 NOV 2008
- Manuscript Accepted: 27 AUG 2008
- Manuscript Revised: 26 AUG 2008
- Manuscript Received: 28 APR 2008
Funded by
- FWF-Grants. Grant Numbers: 15943, 19240, 19664
- Abstract
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- Cited By
Keywords:
- Macrophage;
- Nitric oxide;
- Nramp1;
- Salmonella;
- Slc11a1
Abstract
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-α 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-α 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.