Influence of Slc11a1 (formerly Nramp1) on DSS-induced colitis in mice.
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.
Jiang
Hui-Rong
HR
Centre for Child Health Research, University of Western Australia, P.O. Box 855, West Perth, Western Australia, 6872, Australia.
Gilchrist
Derek S
DS
Popoff
Jean-Francois
JF
Jamieson
Sarra E
SE
Truscott
Martha
M
White
Jacqueline K
JK
Blackwell
Jenefer M
JM
D000818:Animals; D027682:Cation Transport Proteins / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016264:Dextran Sulfate / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000032:analysis; D053765:Interleukin-12 Subunit p35 / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008198:Lymph Nodes; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen; D000099173:Natural Resistance-associated Macrophage Protein 1
D027682:Cation Transport Proteins; D016264:Dextran Sulfate; D007371:Interferon-gamma; D016753:Interleukin-10; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D012333:RNA, Messenger; D000099173:Natural Resistance-associated Macrophage Protein 1