近日，来自比利时VIB研究所的研究人员发现，糖皮质激素受体的二聚化能够诱导MAPK磷酸酶1来抵御TNK诱导的炎症反应。
糖皮质激素（GCS）是由肾上腺皮质中束状带分泌的一类甾体激素，主要为皮质醇（cortisol），具有调节糖、脂肪、和蛋白质的生物合成和代谢的作用，还具有抑制免疫应答、抗炎、抗毒、抗休克作用。
研究发现，糖皮质激素通过与糖皮质激素受体(GR)的作用抑制了肿瘤坏死因子（TNF）诱导的致命的炎症反应。在该研究里，他们发现GR的二聚化在降低TNF敏感性中起着重要作用。
在GR不能够二聚化的突变小鼠，他们发现，TNF不能诱导MAPK磷酸酶1(MKP1)。利用Mkp1–/–小鼠，他们评估了TNF的敏感性。结果发现，肝脏内炎症基因诱导增加，循环的细胞因子也增加，然后肠上皮细胞死亡，继而表现出严重的肠炎及低体温症，最后死亡。
氨基末端激酶（JNK）能够促进凋亡，在肝脏组织，Mkp1–/–小鼠的磷酸化JNK水平增加。为此，他们进一步研究了JNK缺陷小鼠对TNF的应答反应。结果发现，Jnk1–/–小鼠对TNF的敏感性没有显著变化，但是，Jnk2–/–小鼠却能够显著的抵御TNF，这表明在TNF诱导的炎症反应中JNK2具有至关重要的作用。
此外，他们还发现，在没有Jnk2的Mkp1–/–及突变GR小鼠，其对TNF的提升的敏感性能够被部分缓解。
该研究表明，糖皮质激素受体的二聚化能够通过MPK1来抑制JNK2，免受了TNF诱导的细胞凋亡及致死性炎症反应。（生物谷Deepblue编译）
doi: 10.1172/JCI60006
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Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation
Sofie Vandevyver, Lien Dejager, Tom Van Bogaert, Anna Kleyman, Yusen Liu, Jan Tuckermann and Claude Libert.
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.
