targeted deletion of hif-1α gene in t cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival目标删除hif-1αt细胞中的基因阻止他们在缺氧抑制发炎组织和改善脓毒性小鼠存活率.pdfVIP

Targeted Deletion of HIF-1a Gene in T Cells Prevents their Inhibition in Hypoxic Inflamed Tissues and Improves Septic Mice Survival 1,2. 1,3,4. 2 3 1 1 1,5 3 Manfred Thiel , Charles C. Caldwell , Simone Kreth , Satoshi Kuboki , P. Chen , Patrick Smith , Akio Ohta , Alex B. Lentsch , Dmitry Lukashev1,5, Michail V. Sitkovsky1,5* 1 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Department of Anaesthesiology, Klinikum Grosshadern, University of Munich, Munich, Germany, 3 Trauma, Sepsis and Inflammation Research Group, Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, Ohio, United States of America, 4 Department of Research, Shriner’s Hospital for Children, Cincinnati, Ohio, United States of America, 5 New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts, United States of America Background. 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-1a) in inflamed and hypoxic areas. Methodology/Principal Findings. Using the Cre-lox-P-system we generated mice with a T–cell targeted deletion of the HIF-1a gene and analysed them in an in vivo model of bacterial sepsis. We show that deletion of the HIF-1a gene leads to higher levels of pro-inflammatory cytokines, stronger anti-bacterial effects and much