Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.
Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.
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作者：
丝裂原活化蛋白激酶（MAPK）磷酸酶是双特异性磷酸酶（DUSP），其使MAPK内的磷酸苏氨酸和磷酸酪氨酸残基去磷酸化。DUSP 6优先使细胞外信号调节激酶1和2（ERK 1/2）去磷酸化，使其失活。在这里，我们研究了DUSP 6在结肠中CD 4 + 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，DUSP 6敲除（Dusp 6 −/−）CD 4 + T细胞显示出ERK 1/2活化、增殖、T辅助细胞1分化和IFN-γ产生增加，以及存活率、IL-17 A分泌和调节性T细胞功能显著降低。为了分析DUSP 6在体内的作用，我们采用了Il 10 −/−结肠炎模型，并产生了Il 10 −/−/Dusp 6 −/−双敲除小鼠。Il 10 −/−/Dusp 6 −/−小鼠患有加速和加重的自发性结肠炎，这可以通过抑制ERK 1/2来预防。ERK 1/2抑制也增强了C57 Bl/6和Dusp 6 −/−小鼠体内和体外调节性T细胞的分化。总之，DUSP 6通过抑制TCR依赖性ERK 1/2活化来调节CD 4 + T细胞活化和分化。因此，DUSP 6可能是限制T细胞介导的疾病（如炎症性肠病）中异常T细胞应答的潜在干预靶点。
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 kinase 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 knock out (Dusp6−/−) CD4+ T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation and IFN-γ production, as well as a marked decrease in survival, 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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DOI：
10.4049/jimmunol.1103015
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chang CF;D'Souza WN;Ch'en IL;Pages G;Pouyssegur J;Hedrick SM
通讯作者：
Hedrick SM
影响因子：
32.4
作者：
Cao, Wei;Yang, Yiqing;Zhang, Jingwu Z.
通讯作者：
Zhang, Jingwu Z.
影响因子：
4.8
作者：
Kamakura, S;Moriguchi, T;Nishida, E
通讯作者：
Nishida, E
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.4
作者：
Montufar-Solis, Dina;Schaefer, Jeremy;Klein, John R.
通讯作者：
Klein, John R.