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

Abstract

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.

Clinico-Biological Implications of Modified Levels of Cytokines in Chronic Lymphocytic Leukemia: A Possible Therapeutic Role

“…Other studies demonstrated that TNF stimulates the growth of leukemic B cells and has action in the progression of B-CLL [68,69].…”

“…IL-21 Antitumoral Increased apoptosis [55][56][57][58][59][60] Increased proliferation of cytotoxic T cells [61,62] IL-22 Protumoral Stimulation of STAT3 [63][64][65][66] Reduced apoptosis [63][64][65][66] IL-23 Protumoral Unclear [67] TNF-alpha Protumoral Increased proliferation [68,69] STAT: Signal Transducer and Activator of Transcription; INKT: invariant Natural Killer; VEGF: Vascular Endothelial Cell Growth Factor; BCL-2: B-cell lymphoma 2; NK: Natura Killer; IL: Interleukin; TNF: Tumour Necrosis Factor.…”

TNF: A master switch for inflammation to cancer

“…TNF-alpha antagonists may have therapeutic potential in this malignancy. TNF-alpha is constitutively produced by B-cell chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) cells and may play a relevant role in these diseases (52). These conclusions are based on the presence of circulating levels of TNF-alpha in the serum of 20 of the 24 patients tested, with undetectable values found in normal sera.…”

True

“…Furthermore the secretion of cytokines by B-CLL cells themselves could also influence parallel specific immune responses. 40,41 Nevertheless, the inhibition of T cell/B cell interaction by B-CLL described here, seems not to involve cytokine secretion (Figure 4).…”