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The Journal of Immunology, 2006, 176: 5471-5477.
Copyright © 2006 by The American Association of Immunologists

TAT-BH4 and TAT-Bcl-xL Peptides Protect against Sepsis-Induced Lymphocyte Apoptosis In Vivo1

Richard S. Hotchkiss2,*,{ddagger},§, Kevin W. McConnell{ddagger}, Kristin Bullok§, Christopher G. Davis*, Katherine C. Chang*, Steven J. Schwulst{ddagger}, Jeffrey C. Dunne*, Gunnar P. H. Dietz||, Mathias Bähr||, Jonathan E. McDunn{ddagger}, Irene E. Karl{dagger}, Tracey H. Wagner*, J. Perren Cobb{ddagger}, Craig M. Coopersmith{ddagger} and David Piwnica-Worms§,||

Departments of * Anesthesiology, {dagger} Medicine, {ddagger} Surgery, § Radiology, and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110; and || Department of Neurology, University of Göttingen, Göttingen, Germany

Apoptosis is a key pathogenic mechanism in sepsis that induces extensive death of lymphocytes and dendritic cells, thereby contributing to the immunosuppression that characterizes the septic disorder. Numerous animal studies indicate that prevention of apoptosis in sepsis improves survival and may represent a potential therapy for this highly lethal disorder. Recently, novel cell-penetrating peptide constructs such as HIV-1 TAT basic domain and related peptides have been developed to deliver bioactive cargoes and peptides into cells. In the present study, we investigated the effects of sepsis-induced apoptosis in Bcl-xL transgenic mice and in wild-type mice treated with an antiapoptotic TAT-Bcl-xL fusion protein and TAT-BH4 peptide. Lymphocytes from Bcl-xL transgenic mice were resistant to sepsis-induced apoptosis, and these mice had a ~3-fold improvement in survival. TAT-Bcl-xL and TAT-BH4 prevented Escherichia coli-induced human lymphocyte apoptosis ex vivo and markedly decreased lymphocyte apoptosis in an in vivo mouse model of sepsis. In conclusion, TAT-conjugated antiapoptotic Bcl-2-like peptides may offer a novel therapy to prevent apoptosis in sepsis and improve survival.




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