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Enhancement of NF-B Activation in Lymphocytes Prevents T Cell Apoptosis and Improves Survival in Murine Sepsis¹

Department of Anesthesiology and Intensive Care, University of Ulm, Ulm, Germany

Sepsis induces extensive lymphocyte apoptosis that contributes to immunosuppression and mortality. Activation of the canonical NF-B pathway, however, prevents TNF-–induced lymphocyte apoptosis. In this study the function of canonical NF-B in T cells was studied in the context of murine sepsis. Upon cecal ligation and puncture (CLP), NF-B DNA binding activity in thymocytes declines relative to sham-operated mice. This decline in NF-B 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-B-dependent antiapoptotic genes Bcl-x_L and c-IAP2 is suppressed upon sepsis induction. Interestingly, adoptive transfer of IB-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-B ameliorates immunosuppression during murine sepsis. These data provide evidence for a new approach in sepsis therapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Deutsche Forschungsgemeinschaft (to U.S.).

² Current address: Heart Center, Department of Anesthesiology and Intensive Care II, University of Leipzig, Leipzig, Germany

³ Address correspondence and reprint requests to Dr. Uwe Senftleben, Department of Anesthesiology and Intensive Care, University of Ulm, Steinhövelstr. 9, D-89075 Ulm, Germany. E-mail address: uwe.senftleben{at}uni-ulm.de

⁴ Abbreviations used in this paper: CLP, cecal ligation and puncture; PI, propidium iodide; RIP, receptor interacting protein; HDCA, histone deacetylase; DP, double positive; DN, double negative; wt, wild type.

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