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Interleukin-1ß and Catecholamines Synergistically Stimulate Interleukin-6 Release from Rat C6 Glioma Cells in Vitro: a Potential Role for Lysophosphatidylcholine

Department of Chemistry, University of Nevada Las Vegas, Las Vegas, Nevada 89154-4003

Address all correspondence and requests for reprints to: Bryan L. Spangelo, Department of Chemistry, University of Nevada Las Vegas, 4505 Maryland Parkway, Las Vegas, Nevada 89154-4003. E-mail: spangelb{at}nevada.edu

Interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) are proinflammatory cytokines that affect the secretion of several neuroendocrine hormones. In addition, glial cells synthesize and release IL-6, suggesting a paracrine role for this cytokine in the brain. We have examined the regulation of IL-6 release from glial cells by cytokines and catecholamines. Forty ng/ml IL-1ß induced a maximal 30-fold stimulation of IL-6 release (P < 0.01); higher and lower concentrations of IL-1ß were less effective. In the presence of (Bu)₂cAMP, IL-1ß induced a strongly synergistic response with respect to IL-6 release; thus, the combination of these two agents resulted in a release of IL-6 that was much larger that the release attributed to either agent alone (i.e. 30-fold higher). Similarly, the combination of IL-1ß and the diterpene forskolin (but not the inactive analog 1,9-dideoxyforskolin) or cholera toxin also resulted in a synergistic stimulation of C6 glioma IL-6 release. Thus, increases in intracellular cAMP concentrations act in a synergistic fashion with the IL-1ß signaling pathway for IL-6 release. Because catecholamines increase intracellular cAMP levels, we investigated the effects of dopamine, epinephrine, and norepinephrine on IL-6 release. The combination of 1.0 to 100 µM of each catecholamine with IL-1ß resulted in the synergistic stimulation of IL-6 release. The coincubation of the ß-agonist isoproterenol and IL-1ß resulted in a striking 25-fold synergistic induction of IL-6 release. The synergistic increases in IL-6 release caused by IL-1ß and isoproterenol as well as IL-1ß and norepinephrine were blocked by the pretreatment of C6 cells with the ß-receptor antagonist propranolol. Because lysophosphatidylcholine (LPC) may function as a second messenger for IL-1ß, we also investigated the effects of LPC. Exogenous LPC (5 to 40 µM) stimulated IL-6 release from C6 glioma cells in a concentration-related manner (P < 0.01). The coincubation of LPC with norepinephrine provoked a synergistic release in IL-6 comparable with that obtained with IL-1ß and norepinephrine. Exposure of [³H]choline-labeled C6 cells to IL-1ß resulted in an increase in the [³H]LPC species as well as a decrease in [³H]phosphatidylcholine. Finally, while TNF was less efficacious than IL-1ß for the stimulation of IL-6 release from C6 cells, the combination of IL-1ß and TNF resulted in a significant synergistic induction of IL-6 release. We have demonstrated that IL-1ß stimulates IL-6 release from rat C6 glioma cells via a noncAMP-mediated mechanism that may involve LPC. The synergistic induction by cytokines and catecholamines of glial cell-derived IL-6 may subsequently affect inflammatory, neurodegenerative or neurotropic processes in the CNS.

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