title: Interleukin-6 inhibits apoptosis and tumour necrosis factor induced proliferation of B-chronic lymphocytic leukaemia.
abstract: There is now good evidence that tumour necrosis factor [TNF] stimulates DNA synthesis of B-chronic lymphocytic leukaemia (B-CLL) cells. The malignant clone produces TNF, and addition of exogenous TNF up-regulates the TNF mRNA in B-CLL cells. Interleukin-6 (rIL-6) may also be important in this growth loop. We studied the interaction of TNF and IL-6 in the regulation of DNA synthesis (3H-TdR uptake), cytokine release and cell survival in CLL cells in vitro. Addition of TNF (100 U/ml over 5 days) enhanced DNA synthesis from 718 +/- 284 (mean cpm +/- SE) to 2730 +/- 545 compared to cells cultured in medium alone (n = 16, p < 0.01). TNF-alpha induced DNA synthesis was inhibited in all cases studied by the addition of anti-TNF monoclonal antibody (5 micrograms/ml) to cell cultures. Spontaneous IL-6 protein release was enhanced in the presence of TNF (100 U/ml and 250 U/ml) by CLL cells at 48 hours of culture 143.6% and 172% (p < 0.05, n = 6). At 120 hours of culture, the increase was 323% and 412.5% (4 of 7 cases) of the control respectively. IL-6 (100 U/ml or greater) increased spontaneous DNA synthesis (3H-TdR uptake) but, in the presence of high concentrations of TNF-alpha, inhibited TNF induced DNA synthesis in a dose dependent manner. Cell survival was reduced in the presence of anti-IL-6 mAb, while IL-6 was able to protect CLL cells from spontaneous apoptosis. These results suggest that IL-6 in an autocrine manner may inhibit DNA synthesis but prolongs survival in CLL cells. Increased serum IL-6 levels were detected in 27 of 50 cases of CLL, the mean level being significantly higher in Rai Stage III and IV cases compared to Rai Stage O-II cases.
authors.affiliation: Department of Haematology, Royal Free Hospital School of Medicine, London, England, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Reittie
authors.forename: K L
authors.initials: KL
authors.lastname: Yong
authors.forename: P
authors.initials: P
authors.lastname: Panayiotidis
authors.forename: A V
authors.initials: AV
authors.lastname: Hoffbrand
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D004273:DNA, Neoplasm; D006131:Growth Inhibitors; D015850:Interleukin-6; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors