期刊
MUCOSAL IMMUNOLOGY
卷 8, 期 3, 页码 505-515出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mi.2014.84
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资金
- Institute of Health Carlos III (Madrid, Spain) [CP10/00417]
- Crohn's and Colitis Foundation of America (CCFA) [2746]
- FISABIO research foundation (Valencia, Spain) [C-05/2012]
- US National Institutes of Health [AI095623, DK35108]
Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6(-/-)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-c production, as well as a marked decrease in survival, interleukin-17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(-/-) model of colitis and generated Il10(-/-) /Dusp6(-/-) double-knockout mice. Il10(-/-) /Dusp6(-/-) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(-/-) mice. In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.
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