Enhancement of NF-kappaB activation in lymphocytes prevents T cell apoptosis and improves survival in murine sepsis.

Abstract

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.

• Authors: Heinrich V Groesdonk, Florian Wagner, Beatrix Hoffarth, Michael Georgieff, Uwe Senftleben
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 12 Pg. 8083-9 (Dec 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 18056349 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• I-kappa B Kinase

Topics

• Animals
• Apoptosis (genetics)
• Gene Expression Regulation
• I-kappa B Kinase (deficiency, genetics)
• Mice
• Mice, Mutant Strains
• NF-kappa B (metabolism)
• Sepsis (immunology)
• Signal Transduction
• Survival Analysis
• T-Lymphocytes (immunology)
• Thymus Gland (immunology)