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双特异性磷酸酶6调节CD4+ T细胞功能并抑制白细胞介素-10缺陷小鼠的自发性结肠炎。

Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.

作者信息

Bertin S, Lozano-Ruiz B, Bachiller V, García-Martínez I, Herdman S, Zapater P, Francés R, Such J, Lee J, Raz E, González-Navajas J M

机构信息

Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.

Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.

出版信息

Mucosal Immunol. 2015 May;8(3):505-15. doi: 10.1038/mi.2014.84. Epub 2014 Sep 17.

DOI:10.1038/mi.2014.84
PMID:25227984
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4363301/
Abstract

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-γ 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.

摘要

丝裂原活化蛋白激酶（MAPK）磷酸酶是双特异性磷酸酶（DUSP），可使MAPK中的磷酸苏氨酸和磷酸酪氨酸残基去磷酸化。DUSP6优先使细胞外信号调节激酶1和2（ERK1/2）去磷酸化，使其失活。在此，我们研究DUSP6在结肠中CD4(+) T细胞功能、分化和炎症特征中的作用。在T细胞受体（TCR）刺激后，DUSP6基因敲除（Dusp6(-/-)）的CD4(+) T细胞显示出ERK1/2激活增加、增殖、辅助性T细胞1分化和干扰素-γ产生增加，以及存活率、白细胞介素-17A（IL-17A）分泌和调节性T细胞功能显著降低。为了分析DUSP6在体内的作用，我们采用了Il10(-/-)结肠炎模型并生成了Il10(-/-)/Dusp6(-/-)双基因敲除小鼠。Il10(-/-)/Dusp6(-/-)小鼠患有加速和加重的自发性结肠炎，ERK1/2抑制可预防这种情况。ERK1/2抑制在体外和体内也增强了C57Bl/6和Dusp6(-/-)小鼠的调节性T细胞分化。总之，DUSP6通过抑制TCR依赖性ERK1/2激活来调节CD4(+) T细胞的激活和分化。因此，DUSP6可能是限制T细胞介导疾病（如炎症性肠病）中异常T细胞反应的潜在干预靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba02/4363301/4a45ea54294f/nihms621373f6.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba02/4363301/4a45ea54294f/nihms621373f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba02/4363301/db7dc2fe7538/nihms621373f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba02/4363301/1126f508fb44/nihms621373f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba02/4363301/0fdc9300f938/nihms621373f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba02/4363301/1911ca005417/nihms621373f4.jpg
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