Inhibition of endothelial cell growth by macrophage-like U-937 cell-derived oncostatin M, leukemia inhibitory factor, and transforming growth factor beta1

Conditioned media were collected from phorbol ester-treated human macrophage-like U-937 cells and analyzed for the presence of inhibitors of endothelial cell (EC) proliferation. By a combination of ion exchange and reverse-phase liquid chromatography, three inhibitors were purified to homogeneity as ascertained by microsequencing of 14-17 N-terminal amino acids. These inhibitors were identified as oncostatin M (OSM), leukemia inhibitory factor (LIF), and transforming growth factor beta1 (TGF-beta1). The identities of the three EC growth inhibitors were confirmed by demonstrating that recombinant human OSM, LIF, and TGF-beta1 were inhibitory in the same concentration range. Inhibition of EC proliferation by OSM was a newly described property of this cytokine. OSM was the most potent inhibitor with a half-maximal inhibition by recombinant material of 0.15-.2 ng/ml compared with 0.6-0.9 and 0. 9-1.0 ng/ml for LIF and TGF-beta1, respectively. The three factors inhibited basal, vascular endothelial cell growth factor-stimulated, and fibroblast growth factor 2-stimulated EC proliferation. Interleukin-6 and ciliary neurotrophic factor, two cytokines related structurally to OSM and LIF, were not active as EC growth inhibitors. It was concluded that macrophage-like cells secrete a variety of potent EC growth inhibitors and that one of these, OSM, is among the most potent EC growth inhibitors yet reported.