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Molecular and Cellular Biology, August 2005, p. 6363-6379, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6363-6379.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Death Receptor-Induced Signaling Pathways Are Differentially Regulated by Gamma Interferon Upstream of Caspase 8 Processing

Daniela Siegmund,¹ Andreas Wicovsky,¹ Ingo Schmitz,² Klaus Schulze-Osthoff,² Sebastian Kreuz,³ Martin Leverkus,⁴ Oliver Dittrich-Breiholz,⁵ Michael Kracht,⁵ and Harald Wajant^1*

Department of Molecular Internal Medicine, Medical Polyclinic, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany,¹ Institute of Molecular Medicine, University of Düsseldorf, Universitäts-Str. 1, 40225 Düsseldorf, Germany,² Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany,³ Laboratory for Experimental Dermatology, Otto-von-Guericke-University Magdeburg, Leipzigerstr. 44, 39120 Magdeburg, Germany,⁴ Institute of Pharmacology, Medical School Hannover, Carl-Neuberg Strasse 1, 30625 Hannover, Germany⁵

Received 25 January 2005/ Returned for modification 22 February 2005/ Accepted 4 May 2005

FasL and gamma interferon (IFN-) are produced by activated T cells and NK cells and synergistically induce apoptosis. Although both cytokines can also elicit proinflammatory responses, a possible cross talk of these ligands with respect to nonapoptotic signaling has been poorly addressed. Here, we show that IFN- sensitizes KB cells for apoptosis induction by facilitating death-inducing signaling complex (DISC)-mediated caspase 8 processing. Moreover, after protection against death receptor-induced apoptosis by caspase inhibition or Bcl2 overexpression, IFN- also sensitized for Fas- and TRAIL death receptor-mediated NF-B activation leading to synergistic upregulation of a variety of proinflammatory genes. In contrast, Fas-mediated activation of JNK, p38, and p42/44 occurred essentially independent from IFN- sensitization, indicating that the apoptosis- and NF-B-related FasL-IFN- cross talk was not due to a simple global enhancement of Fas signaling. Overexpression of FLIP_L and FLIP_S inhibited Fas- as well as TRAIL-mediated NF-B activation and apoptosis induction in IFN--primed cells suggesting that both responses are coregulated at the level of the DISC.

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* Corresponding author. Mailing address: Department of Molecular Internal Medicine, Medical Polyclinic, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany. Phone: 49 (931) 201 71010. Fax: 49 (931) 201 71070. E-mail: harald.wajant{at}mail.uni-wuerzburg.de.

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Molecular and Cellular Biology, August 2005, p. 6363-6379, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6363-6379.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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