Keith Wilson
Faculty Member
Last active: 8/13/2019

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

Singh K, Coburn LA, Barry DP, Asim M, Scull BP, Allaman MM, Lewis ND, Washington MK, Rosen MJ, Williams CS, Chaturvedi R, Wilson KT
Am J Physiol Gastrointest Liver Physiol. 2013 305 (3): G225-40

PMID: 23703655 · PMCID: PMC3742860 · DOI:10.1152/ajpgi.00091.2013

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.

MeSH Terms (15)

Animals Arginine Cationic Amino Acid Transporter 2 Colitis Dextran Sulfate Interleukin-6 Interleukin-17 Interleukin-23 Male Mice Mice, Inbred C57BL Mice, Knockout RNA, Messenger T-Lymphocytes Up-Regulation

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