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- Title
Role of TNFα in bryostatin-induced inhibition of human hematopoiesis.
- Authors
Dräger, A M; van der Hem, K G; Zevenbergen, A; Odding, J H; Huijgens, P C; Schuurhuis, G J
- Abstract
In previous studies bryostatin has been shown to cause dose-dependent stimulatory or inhibitory effects on colony formation in acute myeloid leukemias. In this study we investigated the inhibitory effect of high dose bryostatin-1 (bryo-1) on normal human bone marrow mononuclear cells (BMNC) colony-forming capacity. Preculturing BMNC for 24 h with 250 nM bryo-1 reduced colony formation by 66 ± 11% whereas this treatment did not reduce clonogenic capacity of highly purified CD34[SUP+] BMNC. When precultures with bryo-1 were performed in the presence of several cytokine neutralizing antibodies abrogation of the inhibitory effect could only be demonstrated by anti-TNFα. However, preculturing of BMNC or CD34[SUP+] cells with a wide range of TNFα concentrations as well as TNFα neutralization in supernatant of bryo-1-stimulated BMNC failed to affect the inhibitory effect on CD34[SUP+] cells. Both indicate that TNFα was not the only factor responsible for the inhibitory effect. Depletion of CD14[SUP+] cells from BMNC cultures showed that upon bryo-1 exposure the monocytes served as the main source of TNFα but not as a source of the inhibitory cytokine(s): in CD14[SUP+]-depleted cultures the combination of exogenous added TNFα and bryo-1 resulted in an inhibition of colony formation comparable to that found in crude BMNC. In contrast, purified CD34[SUP+] cultures were not directly affected by bryo-1 and TNFα. However, clonogenic growth of purified CD34[SUP+] cells was inhibited if mononuclear cells were preincubated with TNFα alone for 24 h, and the supernatant of these cultures was used together with bryo-1. These results show that bryo-1-induced inhibition of clonogenic cell growth is not mediated by a direct effect of bryo-1 on CD34 cells but is a result of a process involving production of TNFα by CD14[SUP+] cells upon bryo-1 stimulation together with the induction of (a) secondary factor(s) by TNFα,...
- Subjects
HEMATOPOIESIS; TUMOR necrosis factors
- Publication
Leukemia (08876924), 1999, Vol 13, Issue 1, p62
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/sj.leu.2401250