Oncostatin M production and regulation by human polymorphonuclear neutrophils

Oncostatin M (OSM) is an interleukin-6 (IL-6) family cytokine known in part icular to induce the synthesis of acute-phase proteins by hepatocytes. Beca use human polymorphonuclear neutrophils (PMN) can secrete numerous cytokine s. the potential production of OSM by PMN was investigated. Highly purified PMN were found to contain an intracellular stock of preformed OSM that was rapidly mobilized by degranulating agents such as phorbol myristate acetat e and granulocyte-macrophage colony-stimulating factor (GM-CSF). Moreover, PMN produced OSM after a few hours of stimulation by various agonists. The most potent effect was observed with the combination of lipopolysaccharide and GM-CSF, which had a concentration- and time-dependent effect at both th e protein and mRNA levels. Actinomycin D strongly reduced OSM mRNA inductio n, suggesting the involvement of gene transcription. Cycloheximide inhibite d OSM protein synthesis but did not affect the release of preformed stores. In addition, OSM production was downregulated by dexamethasone, whereas IL -10 had no effect. The OSM produced by PMN was biologically active, as demo nstrated by its ability to induce alpha 1-acid glycoprotein synthesis by He pG2 cells. OSM secretion thus occurs through a two-step mechanism in PMN, c onsisting of early release of a preformed stock, followed by de novo protei n synthesis. This would allow rapid and sustained OSM release to occur at i nflammatory sites, and may contribute to the modulation of local inflammati on. (C) 1999 by The American Society of Hematology.