Cellular proliferation and activation of NF kappa B are induced by autocrine production of tumor necrosis factor alpha in the human T lymphoma line HuT 78.
Tumor necrosis factor (TNF) is a pleiotropic cytokine which has both cytotoxic and proliferative effects. HuT 78, a T-cell line derived from a Sezary lymphoma, is resistant to the cytotoxic effects of TNF, suggesting that TNF may be a growth factor for this cell line. The aim of this study was to determine whether autocrine TNF production could function as a growth factor for HuT 78. Resting HuT 78 and K-4 cells, a protein kinase C-beta-deficient clone of HuT 78, both produced significant amounts of TNF compared with Jurkat cells. Thymidine incorporation by HuT 78 and K-4 cells was inhibited by 90.5 and 73.2%, respectively, with addition of a neutralizing monoclonal antibody to TNF alpha, suggesting that TNF is an autocrine growth factor for these cells. HuT 78 and K-4 cells also expressed high levels of constitutively active NF kappa B, unlike Jurkat cells, which expressed high levels only upon activation with TNF or phorbol 12-myristate 13-acetate. p50 was the major component in the NF kappa B complexes in HuT 78 and K-4 cells. Anti-TNF alpha antibody dramatically decreased levels of NF kappa B in both HuT 78 and K-4 cells. As the TNF gene has an NF kappa B binding motif, an autocrine loop involving TNF induction of NF kappa B is therefore likely in these cells. These findings in a neoplastic T-cell line suggest that therapy directed against TNF could be effective in a subset of T-cell lymphomas.
O'Connell
M A
MA
Department of Clinical Medicine, Trinity College, Dublin, Ireland.
Cleere
R
R
Long
A
A
O'Neill
L A
LA
Kelleher
D
D
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D002460:Cell Line; D002999:Clone Cells; D016384:Consensus Sequence; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D016399:Lymphoma, T-Cell; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000302:isolation & purification / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides; D027702:Organic Cation Transporter 1; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D007375:Interleukin-1; D007376:Interleukin-2; D008565:Membrane Proteins; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D027702:Organic Cation Transporter 1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine