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J. Biol. Chem., Vol. 280, Issue 16, 15635-15643, April 22, 2005

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NFB-dependent Down-regulation of Tumor Necrosis Factor Receptor-associated Proteins Contributes to Interleukin-1-mediated Enhancement of Ultraviolet B-induced Apoptosis^*

Birgit Pöppelmann, Kerstin Klimmek, Elwira Strozyk, Reinhard Voss¶, Thomas Schwarz||, and Dagmar Kulms**

From the Department of Dermatology, University of Münster, Von-Esmarch Strasse 58, D-48149 Münster, the Department of Integrated Functional Genomics, University of Münster, Von-Esmarch Strasse 56, D-48149 Münster, the ^¶Institute of Clinical Chemistry and Laboratory Medicine, University of Münster, Domagkstrasse 6, D-48149 Münster, the ^||Department of Dermatology, University of Kiel, Schittenhelmstrasse 7, D-24105 Kiel, and the ^**Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, D-70569 Stuttgart, Germany

Activation of the transcription factor nuclear factor-B (NFB) by inflammatory cytokines like tumor necrosis (TNF) factor and interleukin-1 (IL-1) is generally associated with the induction of antiapoptotic pathways. Therefore, NFB inhibits both intrinsically and extrinsically induced apoptosis and thus is regarded to act universally in an antiapoptotic fashion. Accordingly, activation of NFB by IL-1 was shown to result in reduction of death ligand-induced apoptosis via up-regulation of antiapoptotic inhibitor of apoptosis proteins (IAPs). In contrast, apoptosis induced by ultraviolet-B radiation (UVB) was shown to be enhanced in an NFB-dependent manner, indicating that NFB can also act in a proapoptotic fashion. This study investigates the molecular mechanisms underlying IL-1-mediated enhancement of UVB-induced apoptosis. We show that NFB activation in costimulation with UVB treatment results in repression of antiapoptotic genes and consequently in down-regulation of the respective proteins, like c-IAP, FLICE-inhibitory protein (FLIP), and some members of the TNF receptor-associated (TRAF)2 protein family. In parallel, TNF is released, leading to activation of signaling pathways mediated by TNF receptor-1 (TNF-R1). Although TNF is well known to induce both proapoptotic and antiapoptotic effects, the down-regulated levels of TRAF-1, -2, and -6 proteins by IL-1 plus UVB action leads to a shift toward promotion of the proapoptotic pathway. In concert with the down-regulation of IAPs and FLIP, TNF-R1 activation as an additional proapoptotic stimulus now results in significant enhancement of UVB-induced apoptosis. Taken together, elucidation of the molecular mechanisms underlying IL-1-mediated enhancement of UVB-induced apoptosis revealed that NFB does not exclusively act in an antiapoptotic fashion but may also mediate proapoptotic effects.

Received for publication, November 17, 2004 , and in revised form, February 11, 2005.

^* This work was supported by the Interdisciplinary Center for Clinical Research, University Münster (Grants IZKF and E10) and the Federal Ministry of Environmental Protection (Grant StSch_4373). 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.

To whom correspondence should be addressed. Tel.: 49-711-685-6995; Fax: 49-711-685-7484; E-mail: Dagmar.Kulms{at}izi.unistuttgart.de.

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