Prostaglandin E2 regulates macrophage colony stimulating factor secretion by human bone marrow stromal cells

Bone marrow stromal cells regulate marrow haematopoiesis by secreting growth factors such as macrophage colony stimulating factor (M-CSF) that regulates the proliferation, differentiation and several functions of cells of the mononuclear-phagocytic lineage. By using a specific ELISA we found that their constitutive secretion of M-CSF is enhanced by tumour necrosis factor-alpha (TNF-alpha). The lipid mediator prostaglandin E-2 (PGE(2)) markedly reduces in a time- and dose-dependent manner the constitutive and TNF-alpha-induced M-CSF synthesis by bone marrow stromal cells. In contrast, other lipid mediators such as 12-HETE, 15-HETE, leukotriene B-4, leukotriene C-4 and lipoxin A(4) have no effect. EP2/EP4 selective agonists (11-deoxy PGE(1) and 1-OH PGE(1)) and EP2 agonist (19-OH PGE(2)) inhibit M-CSF synthesis by bone marrow stromal cells while an EP1/EP3 agonist (sulprostone) has no effect. Stimulation with PGE(2) induces an increase of intracellular cAMP levels in bone marrow stromal cells; cAMP elevating agents (forskolin and cholera toxin) mimic the PGE(2)-induced inhibition of M-CSF production. In conclusion, PGE(2) is a potent regulator of M-CSF production by human bone marrow stromal cells, its effects being mediated via cAMP and PGE receptor EP2\EP4 subtypes. (C) 1999 Elsevier Science B.V. All rights reserved.