Liver X receptor and STAT1 cooperate downstream of Gas6/Mer to induce anti-inflammatory arginase 2 expression in macrophages.
Liver X receptor and STAT1 cooperate downstream of Gas6/Mer to induce anti-inflammatory arginase 2 expression in macrophages.
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DOI：
10.1038/srep29673
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发表时间：
2016-07-13
影响因子：
4.6
通讯作者：
Kang JL
中科院分区：
文献类型：
--
作者：
Kim SY;Lim EJ;Yoon YS;Ahn YH;Park EM;Kim HS;Kang JL
Mer信号通过增加肝脏X受体（LXR）的转录活性来促进急性无菌性炎症的消退。在这里，我们的目的是了解生长抑制特异性蛋白6（Gas 6）治疗后Mer信号传导的下游途径，该途径导致小鼠骨髓源性巨噬细胞（BMDM）中LXR的表达和转录活性。Gas 6诱导的LXRα和LXRβ的增加及其靶基因的表达在来自STAT 1 −/−小鼠的BMDM中或通过STAT 1特异性抑制剂氟达拉滨抑制。Gas 6诱导的STAT 1磷酸化、LXR激活和LXR靶基因表达在Mer−/−小鼠的BMDM中或通过抑制PI 3 K或Akt而受到抑制。Gas 6诱导的Akt磷酸化在来自STAT 1 −/−小鼠的BMDM中或在氟达拉滨存在下被抑制。Gas 6诱导的LXR活性通过LXRα与Arg 2 DNA启动子上的STAT 1相互作用而增强。此外，我们发现，Gas 6抑制脂多糖（LPS）诱导的亚硝酸盐的产生在STAT 1和LXR通路依赖的方式在BMDM。此外，Mer中和抗体减少肺组织中LXR和Arg 2的表达，并增加支气管肺泡灌洗液中NO的产生。我们的数据表明，Gas 6-Mer-PI 3 K/Akt-STAT 1-LXR-Arg 2通路在急性肺损伤的炎症反应中起着重要作用。
Mer signaling increases the transcriptional activity of liver X receptor (LXR) to promote the resolution of acute sterile inflammation. Here, we aimed to understand the pathway downstream of Mer signaling after growth arrest-specific protein 6 (Gas6) treatment that leads to LXR expression and transcriptional activity in mouse bone-marrow derived macrophages (BMDM). Gas6-induced increases in LXRα and LXRβ and expression of their target genes were inhibited in BMDM from STAT1−/− mice or by the STAT1-specific inhibitor fludarabine. Gas6-induced STAT1 phosphorylation, LXR activation, and LXR target gene expression were inhibited in BMDM from Mer−/− mice or by inhibition of PI3K or Akt. Gas6-induced Akt phosphorylation was inhibited in BMDM from STAT1−/− mice or in the presence of fludarabine. Gas6-induced LXR activity was enhanced through an interaction between LXRα and STAT1 on the DNA promoter of Arg2. Additionally, we found that Gas6 inhibited lipopolysaccharide (LPS)-induced nitrite production in a STAT1 and LXR pathway-dependent manner in BMDM. Additionally, Mer-neutralizing antibody reduced LXR and Arg2 expression in lung tissue and enhanced NO production in bronchoalveolar lavage fluid in LPS-induced acute lung injury. Our data suggest the possibility that the Gas6-Mer-PI3K/Akt-STAT1-LXR-Arg2 pathway plays an essential role for resolving inflammatory response in acute lung injury.