Interleukin-2 enhances the production of tumor necrosis factor-α in activated B-type chronic lymphocytic leukemia (B-CLL) cells

L. G. Larsson, M. Carlsson, M. Schena, M. Lantz, F. Caligaris-Cappio, K. Nilsson

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Tumor necrosis factor-α (TNF-α) has recently been implicated as a regulator of growth and differentiation of normal and malignant B cells. We utilized a selected clone (I-83) of primary resting B-type chronic lymphocytic leukemia (B-CLL) cells, inducible to activation, growth and differentiation in vitro, as a model system to study the possible role of TNF-α as an autocrine growth factor for such cells. Our results show that unstimulated I-83 B-CLL cells produced a low level of TNF-α mRNA, as shown by Northern blot analysis, and cytoplasmic TNF-α, determined in individual cells by immunocytochemistry. Secreted TNF-α could, however, not be detected in the medium by ELISA. TNF-α synthesis and secretion was, however, induced to high levels by stimulation of the B-CLL cells with interleukin-2 (IL-2) after activation by 12-O-tetradecanoylphorbol-13-acetate (TPA) or Staphylococcus aureus Cowan strain I (SAC) and B-cell stimulatory factor-MP6 (thioredoxin). A moderate increase in TNF-α secretion was also induced by TPA or IL-2 alone. IL-4 did not have any major effects on the production of TNF-α in activated cells, but inhibited the IL-2-induced production of TNF-α in SAC-activated cells. The cell surface expression of TNF-α receptors (TNF-R), as determined by binding assay using 125I-labelled recombinant TNF-α (rTNF-α), was also induced after SAC or TPA activation, but shed receptors (TNF-binding proteins) were only observed after TPA activation. Exogenously added rTNF-α in combination with TPA or SAC induced a high level of DNA synthesis in I-83 B-CLL cells. The increased endogenous production and secretion of TNF-α during induced growth stimulation, the induced expression of TNF-R, and the mitogenic effect of TNF-α on activated B-CLL cells raise the question whether TNF-α may function as an autocrine co-stimulator of B-CLL cell growth as recently suggested. anti-TNF-α and anti-TNF-R antibodies, however, failed to inhibit the IL-2- and IL-4-induced proliferation of activated I-83 B-CLL cells.

Original languageEnglish
Pages (from-to)226-234
Number of pages9
Issue number2
Publication statusPublished - 1993

ASJC Scopus subject areas

  • Cancer Research
  • Hematology


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