Death receptor-induced signaling pathways are differentially regulated by gamma interferon upstream of caspase 8 processing.
FasL and gamma interferon (IFN-gamma) 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-gamma 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-gamma also sensitized for Fas- and TRAIL death receptor-mediated NF-kappaB 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-gamma sensitization, indicating that the apoptosis- and NF-kappaB-related FasL-IFN-gamma 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-kappaB activation and apoptosis induction in IFN-gamma-primed cells suggesting that both responses are coregulated at the level of the DISC.
Siegmund
Daniela
D
Department of Molecular Internal Medicine, Medical Polyclinic, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
Wicovsky
Andreas
A
Schmitz
Ingo
I
Schulze-Osthoff
Klaus
K
Kreuz
Sebastian
S
Leverkus
Martin
M
Dittrich-Breiholz
Oliver
O
Kracht
Michael
M
Wajant
Harald
H
D017209:Apoptosis / Q000502:physiology; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053222:Fas Ligand Protein; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D007624:KB Cells; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D053418:Death Domain Receptor Signaling Adaptor Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases