Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival.
Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival.
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DOI：
10.1371/journal.pone.0000853
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发表时间：
2007-09-05
期刊：
影响因子：
3.7
通讯作者：
Sitkovsky MV
中科院分区：
文献类型：
--
作者：
Thiel M;Caldwell CC;Kreth S;Kuboki S;Chen P;Smith P;Ohta A;Lentsch AB;Lukashev D;Sitkovsky MV
Sepsis patients may die either from an overwhelming systemic immune response and/or from an immunoparalysis-associated lack of anti-bacterial immune defence. We hypothesized that bacterial superantigen-activated T cells may be prevented from contribution into anti-bacterial response due to the inhibition of their effector functions by the hypoxia inducible transcription factor (HIF-1α) in inflamed and hypoxic areas. Using the Cre-lox-P-system we generated mice with a T–cell targeted deletion of the HIF-1α gene and analysed them in an in vivo model of bacterial sepsis. We show that deletion of the HIF-1α gene leads to higher levels of pro-inflammatory cytokines, stronger anti-bacterial effects and much better survival of mice. These effects can be at least partially explained by significantly increased NF-κB activation in TCR activated HIF-1 α deficient T cells. T cells can be recruited to powerfully contribute to anti-bacterial response if they are relieved from inhibition by HIF-1α in inflamed and hypoxic areas. Our experiments uncovered the before unappreciated reserve of anti-bacterial capacity of T cells and suggest novel therapeutic anti-pathogen strategies based on targeted deletion or inhibition of HIF-1 α in T cells.
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影响因子：
14.9
作者：
Chen KF;Lai YY;Sun HS;Tsai SJ
通讯作者：
Tsai SJ
DOI：
10.1073/pnas.0603493103
发表时间：
2006-09-26
影响因子：
11.1
作者：
Andreakos, E.;Williams, R. O.;Feldmann, M.
通讯作者：
Feldmann, M.
影响因子：
5.3
作者：
Goda, N;Ryan, HE;Johnson, RS
通讯作者：
Johnson, RS
DOI：
10.1073/pnas.0605251103
发表时间：
2006-08-29
影响因子：
11.1
作者：
Ohta, Akio;Gorelik, Elieser;Sitkovsky, Michail
通讯作者：
Sitkovsky, Michail
氧合抑制了生理组织保护机制，从而加剧了急性炎症肺损伤。
影响因子：
9.8
作者：
Thiel, M;Chouker, A;Ohta, A;Jackson, E;Caldwell, C;Smith, P;Lukashev, D;Bittmann, I;Sitkovsky, MV
通讯作者：
Sitkovsky, MV