Interferon-{beta}-induced activation of c-Jun NH{sub 2}-terminal kinase mediates apoptosis through up-regulation of CD95 in CH31 B lymphoma cells
- Department of Immunology and Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, 160-8402, Tokyo (Japan)
- Department of Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, 160-8402, Tokyo (Japan)
- Immunology and Microbiology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582 (Japan)
- Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262 (United States)
Type I interferon (IFN)-induced antitumor action is due in part to apoptosis, but the molecular mechanisms underlying IFN-induced apoptosis remain largely unresolved. In the present study, we demonstrate that IFN-{beta} induced apoptosis and the loss of mitochondrial membrane potential ({delta}{psi}m) in the murine CH31 B lymphoma cell line, and this was accompanied by the up-regulation of CD95, but not CD95-ligand (CD95-L), tumor necrosis factor (TNF), or TNF-related apoptosis-inducing ligand (TRAIL). Pretreatment with anti-CD95-L mAb partially prevented the IFN-{beta}-induced loss of {delta}{psi}m, suggesting that the interaction of IFN-{beta}-up-regulated CD95 with CD95-L plays a crucial role in the induction of fratricide. IFN-{beta} induced a sustained activation of c-Jun NH{sub 2}-terminal kinase 1 (JNK1), but not extracellular signal-regulated kinases (ERKs). The IFN-{beta}-induced apoptosis and loss of {delta}{psi}m were substantially compromised in cells overexpressing a dominant-negative form of JNK1 (dnJNK1), and it was slightly enhanced in cells carrying a constitutively active JNK construct, MKK7-JNK1 fusion protein. The IFN-{beta}-induced up-regulation of CD95 together with caspase-8 activation was also abrogated in the dnJNK1 cells while it was further enhanced in the MKK7-JNK1 cells. The levels of cellular FLIP (c-FLIP), competitively interacting with caspase-8, were down-regulated by stimulation with IFN-{beta} but were reversed by the proteasome inhibitor lactacystin. Collectively, the IFN-{beta}-induced sustained activation of JNK mediates apoptosis, at least in part, through up-regulation of CD95 protein in combination with down-regulation of c-FLIP protein.
- OSTI ID:
- 20717567
- Journal Information:
- Experimental Cell Research, Vol. 304, Issue 2; Other Information: DOI: 10.1016/j.yexcr.2004.11.015; PII: S0014-4827(04)00698-6; Copyright (c) 2004 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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