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Arachidonic acid mediates interferon-gamma-induced sphingomyelin hydrolysis
and monocytic marker expression in HL-60 cell line
D Visnjic, D Batinic and H Banfic
Department of Physiology, School of Medicine, University of Zagreb,
Croatia.
The biochemical signaling mechanisms involved in transducing the effects of
interferon-gamma (IFN-gamma) on human leukemia-derived HL-60 cell
differentiation are not completely understood. Recent studies established
the existence of a sphingomyelin (SM) cycle that operates in response to
the action of IFN-gamma on HL-60 cells, but the mechanisms by which
IFN-gamma induces the SM hydrolysis remain unexplored. In this study,
biochemical events mediating IFN-gamma effects on SM turnover and their
specificity and role in HL-60 differentiation were investigated. The
activation of the SM cycle by IFN-gamma occurred rapidly, with a decrease
of approximately 20% in the SM level observed after 60 minutes with a
concomitant increase in ceramide level. Treatment of HL-60 cells with
IFN-gamma did not influence the 1,2-diacylglycerol concentration,
intracellular Ca2+ concentration, or phospholipase D activity. IFN-gamma
stimulated a rapid release of arachidonic acid (AA) from HL-60 cells; the
effect was abolished by the pretreatment of cells with pertussis toxin,
suggesting a role for a pertussis-toxin-sensitive G protein in
IFN-gamma-mediated activation of phospholipase A2 (PLA2). At 4 to 120 hours
after the stimulation of the cells with IFN-gamma, a significant increase
in the particulate and soluble PLA2 activity was observed, corresponding to
an increase in the level of immunoreactive cPLA2 in both cytosol and
membrane fractions. The treatment of cells with tyrosine kinase inhibitor
herbimycin A completely abolished the effect of IFN-gamma on PLA2 activity
in membrane and cytosolic fractions, but had no effect on
IFN-gamma-mediated early AA release suggesting dual mechanism of PLA2
activation. Melittin, potent activator of PLA2, and AA mimicked the effect
of IFN-gamma on SM hydrolysis. Pretreatment of HL-60 cells with the PLA2
inhibitor, bromophenacyl bromide (BPB), or pertussis toxin abolished the
effect of IFN-gamma on SM hydrolysis; exogenous addition of AA overcame the
effects of BPB and pertussis toxin. Long-term exposure (5 days) of HL-60
cells to IFN-gamma caused an increase in nitroblue tetrazolium
(NBT)-reducing and nonspecific esterase (NSE) activity and induced
expression of Fc gamma RI (CD64) without significant effects on cell
number, adherence, or phagocytic activity. The treatment of cells with AA
or melittin induced NBT, NSE, and CD64 expression to the level similar to
that observed with IFN-gamma, and no further increase was observed with the
combination of IFN-gamma and AA or IFN-gamma and melittin. Treatment of
HL-60 cells with indomethacin, an inhibitor of cyclo-oxygenase, and
nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, had no
effects on IFN-gamma-mediated induction of CD64 expression. These studies
indicate a key role for the phospholipase A2/AA pathway, as an early
biochemical signal elicited by the occupation of IFN-gamma-receptor, in
mediating IFN-gamma induction of the SM cycle and phenotypic changes
associated with differentiation of HL-60 along monocytic lineage.
Volume 89,
Issue 1,
pp. 81-91,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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