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Inhibition of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1
beta (IL-1 beta) messenger RNA (mRNA) expression in HL-60 leukemia cells by
pentoxifylline and dexamethasone: dissociation of acivicin- induced
TNF-alpha and IL-1 beta mRNA expression from acivicin-induced monocytoid
differentiation
JB Weinberg, SN Mason and TS Wortham
VA Center, Department of Medicine, Durham, NC 27705.
We have previously noted that the glutamine antagonist acivicin (alpha
S,5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) induces
monocytoid differentiation of freshly isolated human myeloid leukemia cells
and cells of the myeloid leukemia cell line HL-60, and that the
differentiation is accompanied by increases in expression of tumor necrosis
factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Because we
also showed that TNF-alpha and IL-1 beta can act synergistically to cause
monocytoid differentiation of HL-60 cells, we hypothesized that
acivicin-induced TNF-alpha and IL-1 beta, in an autocrine manner, caused
the differentiation. The purpose of the present study was to determine the
causal roles of TNF-alpha and IL-1 beta in the acivicin-induced
differentiation of HL-60 cells by the use of dexamethasone (DEX) and
pentoxifylline (PTX), two drugs that effectively inhibit expression of
TNF-alpha and IL-1 beta. Acivicin caused a monocytoid differentiation of
the cells as manifest by diminished cell growth, morphologic maturation of
the cells, increased ability to generate hydrogen peroxide in response to
acute treatment with phorbol myristate acetate, and increased expression of
nonspecific esterase and the surface antigens CD14 and CD11b. Acivicin
treatment also caused the cells to have diminished steady-state expression
of messenger RNA (mRNA) for c-myc and c-myb, and increased expression of
mRNA for TNF-alpha and IL-1 beta. DEX and PTX did not alter cell growth,
and did not block the acivicin-induced block in growth. PTX caused a slight
increase in nonspecific esterase expression, but DEX had no effect on this,
and neither drug diminished the acivicin-induced increase in nonspecific
esterase. Although neither drug alone lessened the acivicin enhancement of
hydrogen peroxide production, DEX and PTX together reduced this. DEX did
not modify the acivicin-induced morphologic maturation of the cells, but
PTX alone or PTX with DEX potentiated the acivicin-induced increase in
mature cells. Basal CD14 and CD11b expression were slightly reduced by DEX
and PTX, but neither drug modified the acivicin-induced increases. DEX and
PTX reduced the acivicin-induced increases in TNF-alpha and IL-1 beta mRNA
expression, but they had little or no effect on the acivicin-induced
decreases in expression of mRNA for c-myc and c-myb. Thus, DEX and PTX
effectively block the acivicin-induced expression of TNF-alpha and IL-1
beta, but they have little influence on the acivicin-induced
differentiation process.(ABSTRACT TRUNCATED AT 250 WORDS)
Volume 79,
Issue 12,
pp. 3337-3343,
06/15/1992
Copyright © 1992 by The American Society of Hematology
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