Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia.
Oncostatin-M (OSM), a pluripotent cytokine of the interleukin-6 (IL-6) family, is produced in a number of inflammatory conditions. Known sources of OSM include monocytes-macrophages and T-cells. Here we present microglia, the resident macrophages of the brain, as a source of OSM in the CNS. In this context, we describe a novel inducer of OSM, prostaglandin E(2) (PGE(2)). PGE(2) induces OSM expression in microglia, monocytes, and macrophages of human and murine origin. PGE(2) induction of OSM is mimicked by cholera toxin, an activator of stimulatory G (G(s))-proteins; by forskolin, an activator of adenylate cyclase; and by the cAMP analog, dibutyryl-cAMP. PGE(2) induction of OSM gene expression is inhibited by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, by the protein kinase A (PKA) inhibitor H-89, and by a dominant-negative PKA construct. These data indicate that PGE(2) signals via G(s)-protein-coupled receptor(s), adenylate cyclase, and PKA to induce OSM expression. Accordingly, other activators of cAMP signaling such as norepinephrine and PGE(1) induce OSM. The ability of PGE(2) to induce OSM expression was tested under more physiological conditions, using cocultures of astrocytes and monocytes. Treatment of the cocultures with IL-1beta or tumor necrosis factor-alpha (TNF-alpha) results in production of PGE(2) and OSM. PGE(2) produced in the cocultures is responsible for OSM induction, because pretreatment with indomethacin, an inhibitor of prostaglandin synthesis, as well as depletion of PGE(2), abrogate OSM expression induced by IL-1beta or TNF-alpha. These data suggest that in the CNS, OSM may be produced through collaboration of astrocytes and macrophages-microglia.
Repovic
Pavle
P
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Benveniste
Etty N
EN
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D053683:Oncostatin M; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007375:Interleukin-1; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D012333:RNA, Messenger; D053683:Oncostatin M; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone