Accuri C6 Flow Cytometer System
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Published online before print December 30, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0708397

Received for publication July 3, 2008.
Revised November 10, 2008.
Accepted for publication December 3, 2008.

Article

Influence of Slc11a1 (formerly Nramp1) on DSS-induced colitis in mice

Hui-Rong Jiang *{dagger}, Derek S. Gilchrist {dagger}, Jean-Francois Popoff *, Sarra E. Jamieson *{ddagger}, Martha Truscott *, Jacqueline K. White *, and Jenefer M. Blackwell *{ddagger}@

*Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Cambridge, United Kingdom; {dagger}Division of Immunology, Infection & Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; and {ddagger}Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, West Perth, Western Australia

@ To whom correspondence should be addressed. E-mail: jblackwell{at}ichr. uwa.edu.au.


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Abstract

Multiple genetic studies in humans indicate a role for solute carrier family 11a member 1 [SLC11A1; formerly natural resistance-associated macrophage protein 1 (NRAMP1)] in autoimmune disease susceptibility, including ulcerative colitis. Murine Slc11a1 has many pleiotropic effects on macrophage activation and proinflammatory responses. To determine which of these are important in ulcerative colitis, we established a phenotype for oral dextran sulfate sodium (DSS)-induced acute colitis in congenic Slc11a1 wild-type (wt) and mutant (mt) mice on a B10 background. For over 7 days of treatment with 2% DSS in the drinking water, Slc11a1 wt mice showed enhanced acute ulcerative colitis, as demonstrated by significantly greater body weight loss and reduction in colon length, as well as a marked increase in monocyte/macrophage inflammatory infiltrates and histopathology changes in the colon. This was accompanied by a clear, inverse relationship between IFN-{gamma} and IL-10 responses in Slc11a1 wt compared with mt mice, resulting in a significantly higher ratio of IFN-{gamma}:IL-10 in wt compared with mt mice in lymph node and splenic T cells. RNase protection assays confirmed the presence of significantly higher IFN-{gamma} at the RNA level in the colons of wt compared with mt mice at Day 7 of treatment. Interestingly this was accompanied by significantly enhanced RNA levels for the acute-phase protein IL-6, which is known to inhibit the generation of forkhead box P3+ regulatory T cells and help to drive the differentiation of Th17 from naive T cells and not by differences in RNA for IL-12p35 or IL-12p40 molecules that dimerize to form the Th1-inducing cytokine IL-12.

Key Words: proinflammatory response • inflammatory bowel disease