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Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic
leukemia cells: a possible regulatory role of TNF in the progression of the
disease
R Foa, M Massaia, S Cardona, AG Tos, A Bianchi, C Attisano, A Guarini, PF di Celle and MT Fierro
Dipartimento di Scienze Biomediche e Oncologia Umana, University of Torino,
Italy.
Tumor necrosis factor-alpha (TNF) is a cytokine that displays a pleomorphic
array of effects on different cell populations. Evidence is presented that
TNF may be constitutively produced by B-cell chronic lymphocytic leukemia
(B-CLL) and hairy cell leukemia (HCL) cells and that it may play a relevant
role in these diseases. These conclusions are based on the presence of
circulating levels of TNF in the serum of 20 of the 24 patients tested
(83.3%), while undetectable values were found in normal sera. The
suggestion that the increased serum levels were due to the leukemic cell
population is strengthened by the evidence that purified B-CLL and HCL
cells may constitutively release variable degrees of TNF. These levels
markedly increase after incubation with interferon gamma or
phytohemagglutinin (PHA) plus phorbol myristate acetate (PMA). The cellular
release of TNF by primary B-CLL cells was significantly (P less than .001)
higher in B-CLL stage O-I patients compared with stage II-III patients. The
demonstration that, in B-cell chronic lymphoproliferative disorders, the
pathologic cells may release TNF was further confirmed by the presence of
the mRNA for this cytokine in primary and/or in pre-activated cells.
Recombinant TNF was capable of inducing a proliferative signal only in a
minority of cases (4/24); in most cases it was ineffective, and, in a few,
it reduced the degree of proliferation. Furthermore, in costimulatory
experiments with interleukin-2 and PHA plus PMA, TNF was ineffective. On
the other hand, when primary B-CLL cells were incubated in the presence of
an anti-TNF antibody, in 8 of 12 independent experiments a 2- to 15-fold
increase in thymidine uptake was documented. Taken together, these results
suggest that TNF may play a regulatory role in the progression of the
neoplastic clone in B-cell chronic lymphoproliferative disorders and may be
implicated in some of the side effects associated with these diseases.
Volume 76,
Issue 2,
pp. 393-400,
07/15/1990
Copyright © 1990 by The American Society of Hematology
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