Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation.
Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation.
复制标题
DOI：
10.1172/jci60006
复制
发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Sofie Vandevyver;L. Dejager;Tom Van Bogaert;A. Kleyman;Yusen Liu;J. Tuckermann;C. Libert
中科院分区：
文献类型：
--
作者：
Sofie Vandevyver;L. Dejager;Tom Van Bogaert;A. Kleyman;Yusen Liu;J. Tuckermann;C. Libert
糖皮质激素通过糖皮质激素受体(GR)发挥作用，抑制肿瘤坏死因子诱导的致死性炎症。在这里，我们证明了GR二聚化在降低肿瘤坏死因子敏感性中的作用。在不能使GR二聚化的突变小鼠中，我们发现肿瘤坏死因子不能诱导MAPK磷酸酶1(Mkp1)。我们评估了mkp1(-/-)小鼠对肿瘤坏死因子的敏感性，发现肝脏炎症基因诱导增加，循环细胞因子增加，肠上皮细胞死亡，严重的肠道炎症，体温过低和死亡。Mkp1(-/-)小鼠肝组织中磷酸化JNK水平升高，促进细胞凋亡。我们进一步研究了JNK缺陷小鼠对肿瘤坏死因子的反应。虽然JNK1(-/-)小鼠对肿瘤坏死因子的敏感性没有变化，但JNK2(-/-)小鼠对肿瘤坏死因子有显著的保护作用，证明JNK2在肿瘤坏死因子引起的炎症中起着重要作用。此外，我们发现JNK2的缺失部分挽救了mkp1(-/-)和突变型GR小鼠对肿瘤坏死因子的敏感性增加。我们的数据表明，GR二聚化通过Mkp1抑制JNK2，并保护其免受肿瘤坏死因子诱导的细胞凋亡和致死性炎症的影响。
Glucocorticoids acting through the glucocorticoid receptor (GR) inhibit TNF-induced lethal inflammation. Here, we demonstrate that GR dimerization plays a role in reducing TNF sensitivity. In mutant mice unable to dimerize GR, we found that TNF failed to induce MAPK phosphatase 1 (MKP1). We assessed TNF sensitivity in Mkp1(-/-) mice and found increased inflammatory gene induction in livers, increased circulating cytokines, cell death in intestinal epithelium, severe intestinal inflammation, hypothermia, and death. Mkp1(-/-) mice had increased levels of phosphorylated JNK, which promotes apoptosis, in liver tissue. We further examined JNK-deficient mice for their response to TNF. Although Jnk1(-/-) mice showed no change in sensitivity to TNF, Jnk2(-/-) mice were significantly protected against TNF, identifying JNK2 as an essential player in inflammation induced by TNF. Furthermore, we found that loss of Jnk2 partially rescued the increased sensitivity of Mkp1(-/-) and mutant GR mice to TNF. Our data show that GR dimerization inhibits JNK2 through MKP1 and protects from TNF-induced apoptosis and lethal inflammation.