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J. Biol. Chem., Vol. 279, Issue 42, 44005-44011, October 15, 2004

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Transduction of the TAT-FLIP Fusion Protein Results in Transient Resistance to Fas-induced Apoptosis in Vivo^*

Stefan Krautwald, Ekkehard Ziegler, Karen Tiede, Rainer Pust, and Ulrich Kunzendorf

From the Department of Nephrology and Hypertension, University of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany

Although tightly regulated programmed cell death (apoptosis) possesses great importance for tissue homeostasis, several pathologic processes are associated with organ failure due to adversely activated cell apoptosis. Transient increase in apoptosis has been shown to cause organ damage during fulminant hepatitis B, autoimmune diseases, ischemia-reperfusion injury, sepsis, or allograft rejection. A defined and temporary inhibition of cell apoptosis may therefore be of high clinical relevance. Activation of death receptors results in caspase-8 recruitment to the death-inducing signaling complex, which initiates the apoptotic process through cleavage of caspase-8 and downstream substrates. This initial step may be inhibited by the caspase-8 inhibitor FLIP (FLICE inhibitory protein). To specifically inhibit the initiation of death receptor-mediated apoptosis we constructed a fusion protein containing FLIP fused N-terminally to the human immunodeficiency virus TAT domain. This TAT domain allows the fusion protein to cross the cell membrane and thus makes the FLIP domain able to interfere with the death-inducing signaling complex inside of the cell. We observed that incubation of lymphocytic Jurkat or BJAB cells with TAT-FLIP_S proteins significantly inhibits Fas-induced activation of procaspase-8 and downstream caspases, preventing cells from undergoing apoptosis. Systemic application of TAT-FLIP_S prolongs survival and reduces multi-organ failure due to Fas-receptor-mediated lethal apoptosis in mice. Therefore, application of cellular FLIP_S in the form of a TAT fusion protein may open a promising, easily applicable new tool for providing protection against transient, pathologically increased apoptosis in various diseases.

Received for publication, February 6, 2004 , and in revised form, August 10, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft (Bonn, Germany) Grant KU 760/6-1 (to U. K.). 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.

Both of these authors contributed equally to this work.

To whom correspondence should be addressed: University of Schleswig-Holstein, Campus Kiel, Dept. of Nephrology and Hypertension, Schittenhelmstr. 12, 24105 Kiel, Germany. Tel.: 49-431-597-1338; Fax: 49-431-597-1337; E-mail: kunzendorf{at}nephro.uni-kiel.de.

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