近日,，來自比利時VIB研究所的研究人員發(fā)現(xiàn),，糖皮質(zhì)激素受體的二聚化能夠誘導(dǎo)MAPK磷酸酶1來抵御TNK誘導(dǎo)的炎癥反應(yīng),。
糖皮質(zhì)激素（GCS）是由腎上腺皮質(zhì)中束狀帶分泌的一類甾體激素，主要為皮質(zhì)醇（cortisol）,，具有調(diào)節(jié)糖,、脂肪、和蛋白質(zhì)的生物合成和代謝的作用,，還具有抑制免疫應(yīng)答,、抗炎、抗毒,、抗休克作用,。
研究發(fā)現(xiàn)，糖皮質(zhì)激素通過與糖皮質(zhì)激素受體(GR)的作用抑制了腫瘤壞死因子（TNF）誘導(dǎo)的致命的炎癥反應(yīng),。在該研究里,，他們發(fā)現(xiàn)GR的二聚化在降低TNF敏感性中起著重要作用。
在GR不能夠二聚化的突變小鼠,，他們發(fā)現(xiàn),，TNF不能誘導(dǎo)MAPK磷酸酶1(MKP1)。利用Mkp1–/–小鼠,，他們評估了TNF的敏感性,。結(jié)果發(fā)現(xiàn)，肝臟內(nèi)炎癥基因誘導(dǎo)增加,，循環(huán)的細胞因子也增加,，然后腸上皮細胞死亡，繼而表現(xiàn)出嚴重的腸炎及低體溫癥,，最后死亡,。
氨基末端激酶（JNK）能夠促進凋亡，在肝臟組織，Mkp1–/–小鼠的磷酸化JNK水平增加,。為此,，他們進一步研究了JNK缺陷小鼠對TNF的應(yīng)答反應(yīng)。結(jié)果發(fā)現(xiàn),，Jnk1–/–小鼠對TNF的敏感性沒有顯著變化,，但是，Jnk2–/–小鼠卻能夠顯著的抵御TNF,，這表明在TNF誘導(dǎo)的炎癥反應(yīng)中JNK2具有至關(guān)重要的作用,。
此外，他們還發(fā)現(xiàn),，在沒有Jnk2的Mkp1–/–及突變GR小鼠,，其對TNF的提升的敏感性能夠被部分緩解。
該研究表明,，糖皮質(zhì)激素受體的二聚化能夠通過MPK1來抑制JNK2,，免受了TNF誘導(dǎo)的細胞凋亡及致死性炎癥反應(yīng)。（生物谷Deepblue編譯）
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.
