Down regulation of myelopoiesis by mediators inhibiting the production of macrophage-derived granulomonopoietic enhancing activity (GM-EA)

Abstract

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-γ (IFN-γ, 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-γ ≥ PGE2 > 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-γ (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 μg/mL). These results demonstrate that a mechanism for the control of myelopoiesis by mediators such as IFN-γ, 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.