Back to Search
Start Over
Transmembrane TNF-alpha mediates "forward" and "reverse" signaling, inducing cell death or survival via the NF-kappaB pathway in Raji Burkitt lymphoma cells.
- Source :
-
Journal of leukocyte biology [J Leukoc Biol] 2008 Sep; Vol. 84 (3), pp. 789-97. Date of Electronic Publication: 2008 Jun 11. - Publication Year :
- 2008
-
Abstract
- Interestingly, some lymphoma cells, expressing high levels of transmembrane (tm)TNF-alpha, are resistant to secretory (s)TNF-alpha-induced necrosis but sensitive to tmTNF-alpha-mediated apoptosis. As tmTNF-alpha 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-alpha. Using Raji cells as a model, we first added exogenous tmTNF-alpha on fixed, transfected NIH3T3 cells onto Raji cells to examine tmTNF-alpha forward signaling and its effects, showing that constitutive NF-kappaB activity and cellular inhibitor-of-apoptosis protein 1 transcription were down-regulated, paralleled with Raji cell death. As Raji cells express tmTNF-alpha, an inhibition of their tmTNF-alpha expression by antisense oligonucleotide caused down-regulation of NF-kappaB activity. Conversely, increasing tmTNF-alpha expression by suppressing expression of TNF-alpha-converting enzyme that cleaves tmTNF-alpha led to an enhanced activation of NF-kappaB, indicating that tmTNF-alpha, but not sTNF-alpha, contributes to constitutive NF-kappaB activation. We next transfected Raji cells with a mutant tmTNF-alpha lacking the intracellular domain to competitively suppress reverse signaling via tmTNF-alpha; as expected, constitutive NF-kappaB activity was decreased. In contrast, treating Raji cells with sTNFR2 to stimulate reverse signaling via tmTNF-alpha enhanced NF-kappaB activation. We conclude that tmTNF-alpha, when highly expressed on tumor cells and acting as a receptor, promotes NF-kappaB activation through reverse signaling, which is helpful to maintain tumor cell survival. On the contrary, tmTNF-alpha, when acting as a ligand, inhibits NF-kappaB activity through forward signaling, which is inclined to induce tumor cell death.
- Subjects :
- Burkitt Lymphoma immunology
Burkitt Lymphoma metabolism
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Humans
Inhibitor of Apoptosis Proteins genetics
Inhibitor of Apoptosis Proteins metabolism
Luciferases metabolism
NF-kappa B genetics
Oligonucleotides, Antisense pharmacology
RNA, Messenger genetics
RNA, Messenger metabolism
Receptors, Tumor Necrosis Factor, Type II genetics
Receptors, Tumor Necrosis Factor, Type II metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transfection
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha antagonists & inhibitors
Tumor Necrosis Factor-alpha genetics
Apoptosis drug effects
Burkitt Lymphoma pathology
Cell Membrane physiology
Cell Proliferation drug effects
NF-kappa B metabolism
Signal Transduction drug effects
Tumor Necrosis Factor-alpha pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0741-5400
- Volume :
- 84
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of leukocyte biology
- Publication Type :
- Academic Journal
- Accession number :
- 18550789
- Full Text :
- https://doi.org/10.1189/jlb.0208078