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SY Wang, CK Ho, LY Chen, RC Wang, MH Huang, H Castro-Malaspina and MA Moore
Department of Medical Research, Veterans General Hospital, Taipei, Taiwan,
Republic of China.
Monocyte-derived lipid-containing macrophages (MDLMs) constitutively
synthesize a granulomonopoietic enhancing activity (GM-EA) that potentiates
the function of granulocyte-macrophage colony-stimulating activity
(GM-CSA). In the study reported, we show that GM-EA is distinct from
interleukin-1 (IL-1) in biochemical and functional properties and that its
production is negatively regulated by several mediators. Thus, MDLM
cultures pretreated with interferon-gamma (IFN- gamma, 3 to 900 U/mL),
prostaglandin E2 (PGE2, 10(-13) to 10(-8) mol/L), or lactoferrin (LF,
10(-13) to 10(-8) mol/L) invariably produced less GM-EA than untreated
controls. The relative potency of inhibition was in the order of IFN-gamma
greater than or equal to PGE2 greater than LF. The extent of the inhibitory
effects was proportional to dosage and the duration of treatment and could
be observed following only a brief exposure (two hours) of the MDLMS to
physiologic doses of the mediators. Under optimal conditions, IFN-gamma
(300 U/mL for 24 to 48 hours) and PGE2 (10(-9) mol/L for 24 to 48 hours)
could totally abrogate the ability of the MDLMs to produce GM-EA. However,
the drug- inhibited MDLMs could be reactivated to produce GM-EA by
treatment with zymosan (60 micrograms/mL). These results demonstrate that a
mechanism for the control of myelopoiesis by mediators such as IFN-gamma,
PGE2, and LF may involve the inhibition of GM-EA production. Furthermore,
this negative feedback control is reversible and can be overridden when a
proper stimulatory signal is given.
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