The effects of tumor necrosis factor-alpha on early human hematopoietic
progenitor cells treated with 4-hydroperoxycyclophosphamide
J Moreb, JR Zucali and S Rueth
Department of Medicine, University of Florida, Gainesville.
We have previously reported that 20 hours' preincubation of human bone
marrow cells with interleukin-1 beta (IL-1) can protect early progenitor
cells from 4-hydroperoxycyclophosphamide (4-HC) cytotoxicity. Since tumor
necrosis factor-alpha (TNF alpha) shares many of the biologic properties of
IL-1, we have compared the protective effects of TNF alpha with IL-1
against 4-HC. Incubation of human bone marrow mononuclear cells or an
enriched progenitor population for 20 hours with either TNF alpha or IL-1
resulted in the survival of an increased number of single- and
mixed-lineage colonies, including replatable blast cell colonies, while
only rare colonies were seen in the control group. Antibodies to TNF alpha
completely abolished the protection observed with IL-1, while antibodies to
IL-1 alpha and IL-1 beta decreased but did not abolish the protection seen
with TNF alpha. Combinations of low doses of TNF alpha and IL-1 showed
synergy in their protective effects. Furthermore, no protection was
observed by IL-1, IL- 1 bone-marrow-conditioned medium (IL-1-BMCM), or TNF
alpha for HL-60, K562, KG1, KG1a, and DU.528 leukemic-cell lines or primary
acute myelogenous leukemic (AML) blast cells from the lethal effects of
4-HC. In the case of HL-60 and KG1a cell lines, TNF alpha preincubation
resulted in increased cytotoxicity. Furthermore, preincubation of a mixture
of AML cells and normal bone-marrow cells with IL-1 + TNF alpha before 4-HC
resulted in the protection of normal but not leukemic progenitors. These
results suggest that TNF alpha is necessary for the protection of normal,
early, human hematopoietic progenitors from 4-HC, while IL-1 is not
mandatory but will synergize with TNF alpha to offer increased protection.
In addition, no protection from 4-HC is observed by TNF alpha, IL-1, or
IL-1-BMCM for primary leukemic blast cells or leukemic cell lines.
Volume 76,
Issue 4,
pp. 681-689,
08/15/1990
Copyright © 1990 by The American Society of Hematology
