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-γ and IL-10 responses in Slc11a1 wt compared with mt mice, resulting in a significantly higher ratio of IFN-γ: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-γ 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.
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Influence of Slc11a1 (formerly Nramp1) on DSS-induced colitis in mice
Jiang, Hui-Rong; Gilchrist, Derek S.; Popoff, Jean-Francois; Jamieson, Sarra E.; Truscott, Martha; White, Jacqueline K.; Blackwell, Jenefer M.
Follow Journal of Leukocyte Biology
, Volume 85 (4): 703
Fed of American Socs for Experimental Biology – Apr 1, 2009
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