Transmembrane TNF-α mediates “forward” and “reverse” signaling, inducing cell death or survival via the NF-κB pathway in Raji Burkitt lymphoma cells
Open Access
- 11 June 2008
- journal article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 84 (3), 789-797
- https://doi.org/10.1189/jlb.0208078
Abstract
Interestingly, some lymphoma cells, expressing high levels of transmembrane (tm)TNF-α, are resistant to secretory (s)TNF-α-induced necrosis but sensitive to tmTNF-α-mediated apoptosis. As tmTNF-α mediates “forward” as well as “reverse” signaling, we hypothesize that a balanced signaling between forward and reverse directions may play a critical role in determining the fate of cells bearing tmTNF-α. Using Raji cells as a model, we first added exogenous tmTNF-α on fixed, transfected NIH3T3 cells onto Raji cells to examine tmTNF-α forward signaling and its effects, showing that constitutive NF-κB activity and cellular inhibitor-of-apoptosis protein 1 transcription were down-regulated, paralleled with Raji cell death. As Raji cells express tmTNF-α, an inhibition of their tmTNF-α expression by antisense oligonucleotide caused down-regulation of NF-κB activity. Conversely, increasing tmTNF-α expression by suppressing expression of TNF-α-converting enzyme that cleaves tmTNF-α led to an enhanced activation of NF-κB, indicating that tmTNF-α, but not sTNF-α, contributes to constitutive NF-κB activation. We next transfected Raji cells with a mutant tmTNF-α lacking the intracellular domain to competitively suppress reverse signaling via tmTNF-α; as expected, constitutive NF-κB activity was decreased. In contrast, treating Raji cells with sTNFR2 to stimulate reverse signaling via tmTNF-α ehanced NF-κB activation. We conclude that tmTNF-α, when highly expressed on tumor cells and acting as a receptor, promotes NF-κB activation through reverse signaling, which is helpful to maintain tumor cell survival. On the contrary, tmTNF-α, when acting as a ligand, inhibits NF-κB activity through forward signaling, which is inclined to induce tumor cell death.Keywords
Funding Information
- National Natural Science Foundation of China (30471586)
- National Key Basic Research Program of China
- Ministry of Science and Technology of the People’s Republic of China (2004AA215162)
- National Institutes of Health (R01 CA123490)
- Leukemia and Lymphoma Society (6249-05, 6033-08)
This publication has 29 references indexed in Scilit:
- Inhibition of nuclear factor‐κB activation is essential for membrane‐associated TNF‐α‐induced apoptosis in HL‐60 cellsImmunology & Cell Biology, 2006
- SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 productionNature, 2006
- Signalling pathways of the TNF superfamily: a double-edged swordNature Reviews Immunology, 2003
- Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-αNature, 1997
- THE NF-κB AND IκB PROTEINS: New Discoveries and InsightsAnnual Review of Immunology, 1996
- The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activationCell, 1995
- A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptorCell, 1994
- Anti-tumor necrosis factor modulates anti-CD3-triggered T cell cytokine gene expression in vivo.JCI Insight, 1994
- Function and Activation of NF-kappaB in the Immune SystemAnnual Review of Immunology, 1994
- Cell surface tumor necrosis factor (TNF) accounts for monocyte- and lymphocyte-mediated killing of TNF-resistant target cellsCellular Immunology, 1989