Genetic deletion of the HIF-1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model.
Genetic deletion of the HIF-1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model.
复制标题
DOI：
10.1002/eji.201242765
复制
发表时间：
2013-03
影响因子：
5.4
通讯作者：
Lukashev, Dmitriy
中科院分区：
文献类型：
--
作者：
Georgiev, Peter;Belikoff, Bryan G.;Hatfield, Stephen;Ohta, Akio;Sitkovsky, Michail V.;Lukashev, Dmitriy
缺氧-腺苷能抑制和免疫反应的重定向与抗病原体和抗肿瘤免疫的调节有关，其中缺氧诱导因子1α (HIF-1α)起主要作用。在这项研究中，我们研究了异构体I.1 （HIF-1α的定量次要替代异构体）在抗菌免疫和脓毒症存活中的作用。采用盲肠结扎穿刺法建立细菌性腹膜炎模型，研究了I.1同工异构体缺失小鼠和T细胞靶向I.1敲低小鼠在T细胞中的功能。我们发现，I.1亚型的基因缺失导致对脓毒症致死的抵抗力增强，外周血细菌负荷显著降低，M1巨噬细胞极化增加，血清中促炎细胞因子水平增加，抗炎细胞因子IL-10水平显著降低。我们的数据表明，在细菌性败血症期间，I.1异构体在T细胞中具有免疫抑制作用，这是以前未被认识到的。我们将这些数据解释为激活诱导型异构体I.1通过影响M1/M2巨噬细胞极化和杀微生物功能阻碍T细胞对抗菌反应的贡献。
Hypoxia-adenosinergic suppression and re-direction of the immune response has been implicated in the regulation of anti-pathogen and anti-tumor immunity, with Hypoxia-inducible factor 1α (HIF-1α) playing a major role. In this study, we investigated the role of isoform I.1, a quantitatively minor alternative isoform of HIF-1α, in anti-bacterial immunity and sepsis survival. By using the cecal ligation and puncture model of bacterial peritonitis we studied the function of I.1 isoform in T cells using mice with total I.1-isoform deficiency and mice with T cell-targeted I.1 knockdown. We found that genetic deletion of the I.1 isoform resulted in enhanced resistance to septic lethality, significantly reduced bacterial load in peripheral blood, increased M1 macrophage polarization, augmented levels of pro-inflammatory cytokines in serum, and significantly decreased levels of the anti-inflammatory cytokine IL-10. Our data suggest an immunosuppressive role of the I.1 isoform in T cells during bacterial sepsis that was previously unrecognized. We interpret these data as indicative that activation-inducible isoform I.1 hinders the contribution of T cells to the anti-bacterial response by affecting M1/M2 macrophage polarization and microbicidal function.
登录
查看更多内容
DOI：
10.4049/jimmunol.1001567
发表时间：
2011-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Belikoff BG;Hatfield S;Georgiev P;Ohta A;Lukashev D;Buras JA;Remick DG;Sitkovsky M
通讯作者：
Sitkovsky M
影响因子：
2.7
作者：
Lukashev, Dmitriy;Sitkovsky, Michail
通讯作者：
Sitkovsky, Michail
影响因子：
64.5
作者：
Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F
DOI：
10.1161/atvbaha.108.183319
发表时间：
2009-05-01
影响因子：
8.7
作者：
Ben-Shoshan, Jeremy;Afek, Arnon;George, Jacob
通讯作者：
George, Jacob
DOI：
10.4049/jimmunol.1003379
发表时间：
2011-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Haskó G;Csóka B;Koscsó B;Chandra R;Pacher P;Thompson LF;Deitch EA;Spolarics Z;Virág L;Gergely P;Rolandelli RH;Németh ZH
通讯作者：
Németh ZH