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

Authors :
Lori A. Coburn
Keith T. Wilson
Margaret M. Allaman
Brooks Scull
Mohammad Asim
Kshipra Singh
Daniel P. Barry
Nuruddeen D. Lewis
Michael J. Rosen
Christopher S. Williams
Rupesh Chaturvedi
M. Kay Washington
Source :
American journal of physiology. Gastrointestinal and liver physiology. 305(3)
Publication Year :
2013

Abstract

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.

Details

ISSN :
15221547
Volume :
305
Issue :
3
Database :
OpenAIRE
Journal :
American journal of physiology. Gastrointestinal and liver physiology
Accession number :
edsair.doi.dedup.....a10b1eee9ccef94251d07a3a89ae8394