Enhancement of NF-kappaB activation in lymphocytes prevents T cell apoptosis and improves survival in murine sepsis.
Sepsis induces extensive lymphocyte apoptosis that contributes to immunosuppression and mortality. Activation of the canonical NF-kappaB pathway, however, prevents TNF-alpha-induced lymphocyte apoptosis. In this study the function of canonical NF-kappaB in T cells was studied in the context of murine sepsis. Upon cecal ligation and puncture (CLP), NF-kappaB DNA binding activity in thymocytes declines relative to sham-operated mice. This decline in NF-kappaB activity is most likely due to posttranslational modifications such as deacetylation of p65. In parallel, cleavage of procaspase-3 is increased, whereas expression of NF-kappaB-dependent antiapoptotic genes Bcl-xL and c-IAP2 is suppressed upon sepsis induction. Interestingly, adoptive transfer of IkappaBalpha-deficient fetal liver stem cells into sublethally irradiated lymphopenic host mice reduced the decline in thymocyte survival, increased peripheral T cell numbers, and improved the mortality rate relative to wild-type reconstituted hosts after cecal ligation and puncture. In conclusion, lymphocyte-directed augmentation of canonical NF-kappaB ameliorates immunosuppression during murine sepsis. These data provide evidence for a new approach in sepsis therapy.
Department of Anesthesiology and Intensive Care, University of Ulm, Ulm, Germany.
Heinrich V
HV
Groesdonk
Florian
F
Wagner
Beatrix
B
Hoffarth
Michael
M
Georgieff
Uwe
U
Senftleben
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology*; D015398:Signal Transduction; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
D016328:NF-kappa B; D051550:I-kappa B Kinase