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.