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Published online before print June 11, 2008

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(Journal of Leukocyte Biology. 2008;84:789-797.)
© 2008 by Society for Leukocyte Biology

Transmembrane TNF- mediates "forward" and "reverse" signaling, inducing cell death or survival via the NF-B pathway in Raji Burkitt lymphoma cells

Hailong Zhang^*,1, Dan Yan^*,1, Xu Shi^*, Huifang Liang^*, Yan Pang^*, Nalin Qin^*, Hui Chen^*, Jing Wang^*, Bingjiao Yin^*, Xiaodan Jiang^*, Wei Feng^*, Wenjie Zhang^*, Muxiang Zhou and Zhuoya Li^*,2

^* Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and
Division of Pediatric Hematology/Oncology/BMT, Emory University School of Medicine, Atlanta, Georgia, USA

² Correspondence: Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd., Wuhan, Hubei, 430030, P.R. China. E-mail: zhuoyali{at}mails.tjmu.edu.cn

Interestingly, some lymphoma cells, expressing high levels of transmembrane (tm)TNF-, are resistant to secretory (s)TNF--induced necrosis but sensitive to tmTNF--mediated apoptosis. As tmTNF- 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-. Using Raji cells as a model, we first added exogenous tmTNF- on fixed, transfected NIH3T3 cells onto Raji cells to examine tmTNF- forward signaling and its effects, showing that constitutive NF-B activity and cellular inhibitor-of-apoptosis protein 1 transcription were down-regulated, paralleled with Raji cell death. As Raji cells express tmTNF-, an inhibition of their tmTNF- expression by antisense oligonucleotide caused down-regulation of NF-B activity. Conversely, increasing tmTNF- expression by suppressing expression of TNF--converting enzyme that cleaves tmTNF- led to an enhanced activation of NF-B, indicating that tmTNF-, but not sTNF-, contributes to constitutive NF-B activation. We next transfected Raji cells with a mutant tmTNF- lacking the intracellular domain to competitively suppress reverse signaling via tmTNF-; as expected, constitutive NF-B activity was decreased. In contrast, treating Raji cells with sTNFR2 to stimulate reverse signaling via tmTNF- ehanced NF-B activation. We conclude that tmTNF-, when highly expressed on tumor cells and acting as a receptor, promotes NF-B activation through reverse signaling, which is helpful to maintain tumor cell survival. On the contrary, tmTNF-, when acting as a ligand, inhibits NF-B activity through forward signaling, which is inclined to induce tumor cell death.

Key Words: tmTNF • sTNF • NF-B • cancer