Respective effects of soluble interleukin-1 receptor and tumour necrosis factor receptor on IL-1 and TNF-alpha-induced DNA synthesis of common acute lymphoblastic leukaemia blasts in vitro.
This study investigates the capacity of human recombinant interleukin-1 alpha (IL-1 alpha), IL-1 beta and tumour necrosis factor-alpha (TNF-alpha) to induce DNA synthesis of highly purified blasts from nine adult common acute lymphoblastic leukaemias (cALL) in 7 d liquid culture. IL-1 alpha, IL-1 beta and TNF-alpha stimulated 3H-TdR uptake in leukaemic blasts in a dose-dependent fashion. The IL-1-induced DNA synthesis of cALL cells could not be prevented by the addition of neutralizing antibodies against IL-3, GM-CSF, IL-6 or TNF-alpha. Similarly, the TNF-alpha-stimulated 3H-TdR incorporation of leukaemic blasts was not affected by the addition of antibodies towards IL-1 alpha, IL-1 beta, IL-3, GM-CSF or IL-6. These observations suggest that IL-1 as well as TNF-alpha stimulated growth could not be attributed to the endogenous production of factors, corresponding to the antibodies used in these experiments. Both IL-1 as well as TNF-alpha mediate their action through interaction with specific cell surface receptors. Recently two distinct types of IL-1 receptors (IL-1-Rs), IL-1R(p80) and IL-1-R(p65), as well as two distinct types of TNF-receptors (TNF-Rs), TNF-R (p55) and TNF-R (p75) have been identified. Both types of TNF-Rs exist also in soluble forms (sTNF-Rs), while soluble IL-1-Rs (sIL-1-Rs) have not yet been found naturally. In this study we show that sIL-1-R as well as sTNF-R modulate the effects of their corresponding cytokine in a dose-dependent bimodal fashion; at lower concentrations they augmented while at higher concentrations they inhibited the cytokine-stimulated DNA synthesis of cALL blasts in vitro. It may therefore be concluded from this study that soluble receptors for both IL-1 and TNF, at least in vitro, are functional and interfere with their corresponding cytokine bioactivity.
Department of Haematology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa.
A
A
Carter
N
N
Haddad
I
I
Draxler
E
E
Israeli
B
B
Raz
I
I
Tatarsky
D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004273:DNA, Neoplasm; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha