Effects of tumour necrosis factor and alpha interferon on chronic B cell malignancies.
Tumour necrosis factor (TNF) induces the lysis of many malignant cells in vitro and regression of some tumours in vivo. However, TNF is also a growth factor for normal fibroblasts, T cells and B cells and we have recently shown that TNF can also act as a growth factor for chronic B cell neoplasms, including hairy cell leukaemia and B-CLL. In these cells it promotes proto-oncogene expression, RNA and DNA synthesis and increases overall cell survival. Stimulation appears to be autocrine in nature since exposure of the neoplastic cells to recombinant TNF protein induces the corresponding messenger RNA and synthesis of the protein itself. TNF induced proto-oncogene expression and DNA synthesis occur over a substantially longer time period than when the cells are stimulated with agents such as TPA and Calcium ionophore (2), but we have no evidence that the delay represents the time taken to generate TNF dependent secondary cytokines such as IL-1 and IL6. Alpha interferon opposes TNF mediated activation and our recent data indicate that this effect is independent of alpha interferon down regulation of TNF receptors. It appears to be related instead to a decreased accumulation of TNF mRNA which occurs contemporaneously with an alpha interferon induced rise in 2-5 A synthetase. If TNF dependent growth is important for the survival of B-CLL cells, then agents which mimic alpha interferon or which block TNF induced autocrine growth would be predicted to be of therapeutic benefit.
Bianchi
A C
AC
Department of Haematology, Royal Free Hospital School of Medicine, London, UK.
Heslop
H E
HE
Drexler
H G
HG
Cordingley
F T
FT
Turner
M
M
De Mel
W C
WC
Hoffbrand
A V
AV
Brenner
M K
MK
D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005246:Feedback; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D007943:Leukemia, Hairy Cell / Q000188:drug therapy / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000494:pharmacology*
D007370:Interferon Type I; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004247:DNA