Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells.
Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells.
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DOI：
10.4049/jimmunol.1003511
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Jope RS
中科院分区：
文献类型：
--
作者：
Beurel E;Yeh WI;Michalek SM;Harrington LE;Jope RS
CD 4 + T细胞对宿主防御至关重要，但也是免疫介导疾病的主要驱动因素。最近，通过鉴定产生IL-17的CD 4 + T细胞的Th 17谱系，对CD 4 + T细胞的Th 1和Th 2亚型的经典观点进行了修订，已发现其在自身免疫性疾病和其他疾病的发病机制中是关键的。控制Th 17细胞分化的机制已被充分描述，但已知用于治疗性减少Th 17细胞的可行靶点很少。Th 17细胞的产生需要IL-6和STAT 3的活化。在CD 4 + T细胞向Th 17细胞极化的过程中，我们发现糖原合成酶激酶-3（GSK 3）的抑制阻断了IL-6的产生、STAT 3的激活和向Th 17细胞的极化。CD 4 + T细胞向Th 17细胞的极化使Th 17细胞中GSK 3 β蛋白水平的表达增加了10倍，而调节性T细胞中的GSK 3 β没有改变。降低GSK 3活性可以直接或分子方式阻断Th 17细胞的产生，而增加GSK 3活性可以促进Th 17细胞的极化。在小鼠体内抑制GSK 3可耗尽肠粘膜中的组成性Th 17细胞，阻断土拉弗朗西斯菌感染后肺中的Th 17细胞生成，并抑制多发性硬化症的实验性自身免疫性脑脊髓炎小鼠模型中脊髓Th 17细胞和疾病症状的增加。这些发现确定GSK 3作为Th 17细胞产生的关键介质，并表明GSK 3抑制剂提供了潜在的治疗干预来控制Th 17介导的疾病。
CD4+ T cells are critical for host defense but are also major drivers of immune-mediated diseases. The classical view of Th1 and Th2 subtypes of CD4+ T cells was recently revised by the identification of the Th17 lineage of CD4+ T cells that produce IL-17, which have been found to be critical in the pathogenesis of autoimmune and other diseases. Mechanisms controlling the differentiation of Th17 cells have been well described, but few feasible targets for therapeutically reducing Th17 cells are known. The generation of Th17 cells requires IL-6 and activation of STAT3. During polarization of CD4+ T cells to Th17 cells, we found that inhibition of glycogen synthase kinase-3 (GSK3) blocked IL-6 production, STAT3 activation, and polarization to Th17 cells. Polarization of CD4+ T cells to Th17 cells increased by 10-fold the expression of GSK3β protein levels in Th17 cells, whereas GSK3β was unaltered in regulatory T cells. Diminishing GSK3 activity either pharmacologically or molecularly blocked Th17 cell production, and increasing GSK3 activity promoted polarization to Th17 cells. In vivo inhibition of GSK3 in mice depleted constitutive Th17 cells in intestinal mucosa, blocked Th17 cell generation in the lung after Francisella tularensis infection, and inhibited the increase in spinal cord Th17 cells and disease symptoms in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. These findings identify GSK3 as a critical mediator of Th17 cell production and indicate that GSK3 inhibitors provide a potential therapeutic intervention to control Th17-mediated diseases.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
DOI：
10.4049/jimmunol.181.1.338
发表时间：
2008-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
De Sarno P;Axtell RC;Raman C;Roth KA;Alessi DR;Jope RS
通讯作者：
Jope RS
影响因子：
4.4
作者：
Mathur, Anubhav N.;Chang, Hua-Chen;Kaplan, Mark H.
通讯作者：
Kaplan, Mark H.
影响因子：
4.8
作者：
Beurel, Eleonore;Jope, Richard S.
通讯作者：
Jope, Richard S.
影响因子：
7.3
作者：
Martinez, A;Alonso, M;Moreno, FJ
通讯作者：
Moreno, FJ