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-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.

Effect of lymphocytes on the production of granulomonopoietic enhancing factor by fully mature macrophages

“…Resting T cells do not release TNF-dIFN-y and are unable to inhibit GM-EF production. The downregulatory role of IFN-y in GM-EF production has been reported previously [8]. Our present studies further confirm this finding and suggest that the most intense GM-EF suppression induced by activated T cells may be the result of a cooperative effect of TNF-a and IFN-y.…”

“…GM-EF is produced constitutively by fully mature macrophages [5]. It acts specifically on myeloid lineage [6,8,9], targeting on an earlier subpopulation of myeloid progenitor cells, pre-CFU-GM [9], but has no effect on either erythroid (BFU-E) or pluripotent (CFU-GEMM) progenitor cells [6]. The productiodrelease of GM-EF is promoted and suppressed by different regulators involved in myelopoiesis [7,81.…”