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Prostaglandin E2 is a novel inducer of oncostatin-M expression in macrophages and microglia
Pavle Repovic1, Etty N Benveniste
1Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294.
Abstract:
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.
Insights
Microglia in the brain produce Oncostatin-M (OSM) when stimulated by prostaglandin E(2) (PGE(2)). This signaling pathway involves G(s)-proteins and protein kinase A (PKA), suggesting astrocyte-microglia collaboration in CNS inflammation.
Area of Science:
- Neuroimmunology
- Cytokine Biology
- Inflammation Research
Background:
- Oncostatin-M (OSM) is a cytokine in the interleukin-6 (IL-6) family, implicated in inflammatory conditions.
- Monocytes-macrophages and T-cells are known OSM producers.
- Microglia, the brain's resident macrophages, were investigated as a potential source of OSM in the central nervous system (CNS).
Purpose of the Study:
- To identify microglia as a source of OSM in the CNS.
- To investigate prostaglandin E(2) (PGE(2)) as a novel inducer of OSM.
- To elucidate the signaling pathway involved in PGE(2)-mediated OSM induction.
Main Methods:
- Investigated OSM expression in human and murine microglia, monocytes, and macrophages.
- Utilized activators of G(s)-proteins (cholera toxin), adenylate cyclase (forskolin), and cAMP analogs (dibutyryl-cAMP).
- Employed inhibitors of adenylate cyclase (2',5'-dideoxyadenosine) and protein kinase A (PKA) (H-89, dominant-negative PKA construct).
- Examined OSM and PGE(2) production in astrocyte-monocyte cocultures stimulated with IL-1beta or TNF-alpha.
- Assessed the role of PGE(2) using indomethacin (prostaglandin synthesis inhibitor) and PGE(2) depletion.
Main Results:
- PGE(2) was identified as a novel inducer of OSM in microglia, monocytes, and macrophages.
- PGE(2) induction of OSM expression involves signaling through G(s)-proteins, adenylate cyclase, and PKA.
- Other cAMP signaling activators, like norepinephrine and PGE(1), also induced OSM.
- In astrocyte-monocyte cocultures, IL-1beta and TNF-alpha induced both PGE(2) and OSM production.
- Inhibition of prostaglandin synthesis or depletion of PGE(2) abrogated IL-1beta/TNF-alpha-induced OSM, confirming PGE(2)'s crucial role.
Conclusions:
- Microglia are a source of OSM in the CNS.
- PGE(2) is a key mediator for OSM induction in CNS myeloid cells via the cAMP/PKA pathway.
- Astrocyte-microglia interactions, involving PGE(2) production, contribute to OSM expression in the CNS during inflammation.