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

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.

• Authors: Hui-Rong Jiang, Derek S Gilchrist, Jean-Francois Popoff, Sarra E Jamieson, Martha Truscott, Jacqueline K White, Jenefer M Blackwell
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 85 Issue 4 Pg. 703-10 (Apr 2009) ISSN: 1938-3673 [Electronic] United States
• PMID: 19116231 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cation Transport Proteins
• Interleukin-12 Subunit p35
• Interleukin-12 Subunit p40
• Interleukin-6
• RNA, Messenger
• natural resistance-associated macrophage protein 1
• Interleukin-10
• Interferon-gamma
• Dextran Sulfate

Topics

• Animals
• Cation Transport Proteins (physiology)
• Colitis (chemically induced, immunology)
• Dextran Sulfate (pharmacology)
• Interferon-gamma (analysis)
• Interleukin-10 (analysis)
• Interleukin-12 Subunit p35 (genetics)
• Interleukin-12 Subunit p40 (genetics)
• Interleukin-6 (genetics)
• Lymph Nodes
• Mice
• RNA, Messenger (analysis)
• Spleen