Death Receptor-Induced Signaling Pathways Are Differentially Regulated by Gamma Interferon Upstream of Caspase 8 Processing
- 1 August 2005
- journal article
- Published by Taylor & Francis in Molecular and Cellular Biology
- Vol. 25 (15) , 6363-6379
- https://doi.org/10.1128/mcb.25.15.6363-6379.2005
Abstract
FasL and gamma interferon (IFN-γ) 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-γ 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-γ also sensitized for Fas- and TRAIL death receptor-mediated NF-κB 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-γ sensitization, indicating that the apoptosis- and NF-κB-related FasL-IFN-γ cross talk was not due to a simple global enhancement of Fas signaling. Overexpression of FLIPL and FLIPS inhibited Fas- as well as TRAIL-mediated NF-κB activation and apoptosis induction in IFN-γ-primed cells suggesting that both responses are coregulated at the level of the DISC.Keywords
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