Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone.
Genomic profile of Toll-like receptor pathways in traumatically brain-injured mice: effect of exogenous progesterone.
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DOI：
10.1186/1742-2094-8-42
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发表时间：
2011-05-08
影响因子：
9.3
通讯作者：
Stein DG
中科院分区：
文献类型：
--
作者：
Hua F;Wang J;Ishrat T;Wei W;Atif F;Sayeed I;Stein DG
创伤性脑损伤（TBI）引起急性炎症反应，导致继发性神经元丢失和行为障碍的持久级联。有报道称，孕酮（PROG）可以抑制脑外伤引起的一些炎症细胞因子和炎症相关因子的增加。toll样受体（TLRs）在免疫/炎症反应的诱导和调节中起着关键作用。因此，在本研究中，我们研究了创伤性脑损伤中tlr介导通路的基因组图谱以及PROG对这些基因的影响。C57BL/6J小鼠双侧额叶内侧皮质撞击损伤。术后1、6 h注射PROG （ig， 16 mg/kg体重）。术后24小时，处死小鼠，取创口周围脑组织进行基因组检测和蛋白质测定。RT-PCR检测了tlr介导通路中84个基因的mRNA表达。采用Western blot、ELISA和免疫组化等方法证实感兴趣基因的蛋白表达。我们发现2个TLRs (TLR1和2)，5个接头/相互作用蛋白（CD14、MD-1、HSPA1a、PGRP和Ticam2）和13个靶基因（Ccl2、Csf3、IL1a、IL1b、IL1r1、IL6、IL-10、TNFa、Tnfrsf1a、Cebpb、cle4e、Ptgs2和Cxcl10）在损伤后显著上调。在TBI后增加的13个靶基因（Ccl-2、IL-1b和Cxcl-10）中，PROG显著下调了其中的3个基因（Ccl-2、IL-1b和cxl -10），但未抑制任何检测到的tlr和接头/相互作用蛋白的表达。相反，PROG上调了1个TLR （TLR9）、5个衔接/相互作用蛋白、5个效应蛋白和10个下游靶基因的表达。我们证实了脑组织中有Ccl-2、Cxcl-10、TLR2和TLR9蛋白的表达，这与我们对mRNA表达的观察结果一致。结果表明，脑外伤可增加tlr介导通路的基因表达。PROG不下调创伤性脑损伤中增加的tlr及其适配蛋白。在TBI急性期，PROG所观察到的炎症细胞因子的减少似乎不是抑制tlr或其接头的结果。
Traumatic brain injury (TBI) causes acute inflammatory responses that result in an enduring cascade of secondary neuronal loss and behavioral impairments. It has been reported that progesterone (PROG) can inhibit the increase of some inflammatory cytokines and inflammation-related factors induced by TBI. Toll-like receptors (TLRs) play a critical role in the induction and regulation of immune/inflammatory responses. Therefore, in the present study, we examined the genomic profiles of TLR-mediated pathways in traumatically injured brain and PROG's effects on these genes. Bilateral cortical impact injury to the medial frontal cortex was induced in C57BL/6J mice. PROG was injected (i.p., 16 mg/kg body weight) at 1 and 6 h after surgery. Twenty-four hours post-surgery, mice were killed and peri-contusional brain tissue was harvested for genomic detection and protein measurement. RT-PCR arrays were used to measure the mRNA of 84 genes in TLR-mediated pathways. Western blot, ELISA and immunohistochemistry were used to confirm the protein expression of genes of interest. We found that 2 TLRs (TLR1 and 2), 5 adaptor/interacting proteins (CD14, MD-1, HSPA1a, PGRP and Ticam2) and 13 target genes (Ccl2, Csf3, IL1a, IL1b, IL1r1, IL6, IL-10, TNFa, Tnfrsf1a, Cebpb, Clec4e, Ptgs2 and Cxcl10) were significantly up-regulated after injury. Administration of PROG significantly down-regulated three of the 13 increased target genes after TBI (Ccl-2, IL-1b and Cxcl-10), but did not inhibit the expression of any of the detected TLRs and adaptor/interacting proteins. Rather, PROG up-regulated the expression of one TLR (TLR9), 5 adaptor/interacting proteins, 5 effectors and 10 downstream target genes. We confirmed that Ccl-2, Cxcl-10, TLR2 and TLR9 proteins were expressed in brain tissue, a finding consistent with our observations of mRNA expression. The results demonstrate that TBI can increase gene expression in TLR-mediated pathways. PROG does not down-regulate the increased TLRs or their adaptor proteins in traumatically injured brain. Reduction of the observed inflammatory cytokines by PROG does not appear to be the result of inhibiting TLRs or their adaptors in the acute stage of TBI.
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影响因子：
3.8
作者：
Harting, Matthew T.;Jimenez, Fernando;Adams, Sasha D.;Mercer, David W.;Cox, Charles S., Jr.
通讯作者：
Cox, Charles S., Jr.
影响因子：
7.5
作者：
Gao, Yin;Fang, Xiubin;Zhang, Baohui
通讯作者：
Zhang, Baohui
影响因子：
4.4
作者：
Chase, Margaret A.;Wheeler, Derek S.;Page, Kristen
通讯作者：
Page, Kristen
影响因子：
5.3
作者：
Naert, Gaelle;Laflamme, Nathalie;Rivest, Serge
通讯作者：
Rivest, Serge
影响因子：
3.3
作者：
Marsh BJ;Williams-Karnesky RL;Stenzel-Poore MP
通讯作者：
Stenzel-Poore MP