Induction of prostaglandin E synthesis in normal and neoplastic macrophages: role for colony-stimulating factor(s) distinct from effects on myeloid progenitor cell proliferation.

Abstract

The biosynthesis of prostaglandin E (PGE) by normal and neoplastic macrophages is intrinsically linked to their synthesis of, and exposure to, myeloid colony-stimulating factors (CS-factors). The defect in responsiveness to endotoxin lipopolysaccharide (LPS) by macrophages from C3H/Hej mice extends equally to the synthesis of CS-factor and PGE. However, C3H/Hej macrophages can be stimulated to synthesize PGE by treatment with agents other than LPS [zymosan, tuberculin purified protein derivative, concanavalin A, poly(I)poly(C)J, which also stimulate CS-factor production, or by the addition of various preparations of soluble CS-factor. In peritoneal wash preparations, constitutive PGE synthesis occurred in rapidly sedimenting macrophage cells, whereas constitutive CS-factor production and inducible PGE synthesis occurred in slower sedimenting adherent cells. A similar functional heterogeneity in CS-factor and PGE production was found in neoplastic macrophage cell lines. The association of elevated CS-factor levels atnd PGE synthesis by macrophages suggests a role for CS-factor in many of the physiological responses heretofore associated w' ith elevated tissue levels of the E type prostaglandins.The growth and maturation of myeloid progenitor cells in vitro depends upon a class of regulatory proteins termed colonystimulating factor(s) [CS-factor(s)] (1, 2). The elaboration of CS-factors by mononuclear phagocytes (3-5), particularly after their exposure in vitro to agents-such as bacterial endotoxin (6, 7)-that elevate serum CS-factor levels and stimulate granulocyte and monocyte-macrophage formation in vivo (8, 9) has implicated the blood monocyte and tissue macrophage as the primary CS-factor-producing cell population. Clonal proliferation of both granulocyte-macrophage progenitor cells (1) and macrophage precursor cells (10) in'semisolid medium is the usual bioassay for the regulatory action of CS-factors.We recently showed that increasing concentrations of a source of CS-factor progressively stimulated prostaglandin E AGE) synthesis by human and murine macrophages (11). The endotoxin promotion of CS-factor production was also correlated with increased PGE synthesis by macrophages (12

Prostaglandin E inhibition of T-lymphocyte colony formation: a possible mechanism of monocyte modulation of clonal expansion.

“…As further evidence of the complexity of prostaglandin effect, the addition of PGF2G, to the mononuclear cell cultures gave a different response. Whereas low concentrations of PGF2G showed dose-dependent stimulation of colony formation, at the higher concentrations tested PGF2c, (10 ,M) was inhibitory. This inhibition may have been a result of PGE2 contamination or a PGE2-like effect seen at high doses of PGF2<,.…”

“…As part of a probable physiological control to prevent runaway myelopoiesis, monocyte/ macrophage PGE2 synthesis is initiated (3,9). When highly purified colony-stimulating factor was tested it could be shown to directly cause PGE2 synthesis (10). Thus myelopoiesis appears to be regulated by two diffusable, monocyte/macrophage-derived agents with the specificity residing in the positive limb of the dual feedback loop.…”

Association between colony forming units-granulocyte macrophage expression of Ia-like (HLA-DR) antigen and control of granulocyte and macrophage production. A new role for prostaglandin E.

“…Kinetic analysis indicates that constitutive prostaglandin E production by mouse macrophages (26) and human monocytes is not detected during the first 3 h in culture. These results negate the contribution of endogenously produced prostaglandin E in this system.…”

“…The ultimate degree of CFU-GM expansion to mature granulocytes and macrophages is dependent upon GM-CSF levels (32,33). At high prostaglandin concentrations, particularly as a consequence of GM-CSF induced monocyte-macrophage prostaglandin production (20,26,28,34), clonal CFU-GM expansion is limited (8)(9)(10)28) …”

Effect of host-cell interactions on clonogenic carcinoma cells in human malignant effusions

“…We cannot exclude the possibility that a subpopulation of lymphoid, granulocytic or tumour cells which also adhere might play an accessory role in this growth-stimulatory process. It is possible that tumour cells produce colony-stimulating activity (CSA) (Okabe et al, 1978) which has been shown to be capable of influencing prostaglandin E production (Kurland et al, 1979) and, furthermore, contaminating polymorphonuclear leucocytes can affect CSA by release of lactoferrin (Broxmeyer et al, 1978). However, it has previously been reported that phagocytic depletion alone (which would not remove lymphoid cells) markedly reduces tumour-colony growth (Hamburger et al, 1978) reinforcing the central regulatory role of the macrophage.…”