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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
- 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.
- Subjects :
- Male
Arginine
Physiology
T-Lymphocytes
Inflammation
Granulocyte
Biology
Inflammatory bowel disease
Interleukin-23
Inflammation/Immunity/Mediators
Proinflammatory cytokine
Mice
Physiology (medical)
medicine
Animals
RNA, Messenger
Colitis
Cationic Amino Acid Transporter 2
Mice, Knockout
Hepatology
Interleukin-6
Dextran Sulfate
Interleukin-17
Gastroenterology
medicine.disease
Molecular biology
Up-Regulation
Nitric oxide synthase
Mice, Inbred C57BL
medicine.anatomical_structure
Immunology
biology.protein
Interleukin 17
medicine.symptom
Subjects
Details
- ISSN :
- 15221547
- Volume :
- 305
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Accession number :
- edsair.doi.dedup.....a10b1eee9ccef94251d07a3a89ae8394