Deletion of cationic amino acid transporter 2 exacerbates dextran sulfate sodium colitis and leads to an IL-17-predominant T cell response

American Journal of Physiology - Gastrointestinal and Liver Physiology - Tập 305 Số 3 - Trang G225-G240 - 2013
Kshipra Singh1, Lori A. Coburn1,2, Daniel P. Barry1,2, Mohammad Asim1,2, Brooks Scull1, Margaret M. Allaman1,2, Nuruddeen D. Lewis3,1, M. Kay Washington4, Michael J. Rosen5, Christopher S. Williams3,1,2, Rupesh Chaturvedi1, Keith T. Wilson3,4,1,2
1Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
2Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee
3Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee
4Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
5Division of Gastroenterology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; and

Tóm tắt

l-Arginine (l-Arg) is a semiessential amino acid that has altered availability in human ulcerative colitis (UC), a form of inflammatory bowel disease, and is beneficial in murine colitis induced by dextran sulfate sodium (DSS), a model with similarity to UC. We assessed the role of cationic amino acid transporter 2 (CAT2), the inducible transporter of l-Arg, in DSS colitis. Expression of CAT2 was upregulated in tissues from colitic mice and localized predominantly to colonic macrophages. CAT2-deficient (CAT2−/−) mice exposed to DSS exhibited worsening of survival, body weight loss, colon weight, and histological injury. These effects were associated with increased serum l-Arg and decreased tissue l-Arg uptake and inducible nitric oxide synthase protein expression. Clinical benefits of l-Arg supplementation in wild-type mice were lost in CAT2−/−mice. There was increased infiltration of macrophages, dendritic cells, granulocytes, and T cells in colitic CAT2−/−compared with wild-type mice. Cytokine profiling revealed increases in proinflammatory granulocyte colony-stimulating factor, macrophage inflammatory protein-1α, IL-15, and regulated and normal T cell-expressed and -secreted and a shift from an IFN-γ- to an IL-17-predominant T cell response, as well as an increase in IL-13, in tissues from colitic CAT2−/−mice. However, there were no increases in other T helper cell type 2 cytokines, nor was there a global increase in macrophage-derived proinflammatory cytokines. The increase in IL-17 derived from both CD4 and γδ T cells and was associated with colonic IL-6 expression. Thus CAT2 plays an important role in controlling inflammation and IL-17 activation in an injury model of colitis, and impaired l-Arg availability may contribute to UC pathogenesis.

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American Journal of Physiology - Gastrointestinal and Liver Physiology

Tập 305 Số 3

G225-G240

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