期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 84, 期 3, 页码 789-797出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.0208078
关键词
tmTNF; sTNF; NF-kappa B; cancer
资金
- 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]
- NATIONAL CANCER INSTITUTE [R01CA123490] Funding Source: NIH RePORTER
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-kappa B 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-kappa B 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-kappa B, indicating that tmTNF-alpha, but not sTNF-alpha, contributes to constitutive NF-kappa B 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-kappa B activity was decreased. In contrast, treating Raji cells with sTNFR2 to stimulate reverse signaling via tmTNF-alpha ehanced NF-kappa B activation. We conclude that tmTNF-alpha, when highly expressed on tumor cells and acting as a receptor, promotes NF-kappa B activation through reverse signaling, which is helpful to maintain tumor cell survival. On the contrary, tmTNF-alpha, when acting as a ligand, inhibits NF-kappa B activity through forward signaling, which is inclined to induce tumor cell death.
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