NOREPINEPHRINE AND VASOACTIVE-INTESTINAL-PEPTIDE INDUCE IL-6 SECRETION BY ASTROCYTES - SYNERGISM WITH IL-1-BETA AND TNF-ALPHA

Resident glial cells and invading inflammatory cells are responsible f or cytokine production within the brain. Astrocytes are known to secre te a variety of cytokines upon stimulation with cytokines themselves, protein kinase C activators, bacterial or viral constituents. Astrocyt es also have surface receptors for a wide number of neurotransmitters and neuropeptides and some of these substances affect astrocyte immune functions, such as major histocompatibility complex (MHC) class II an tigen expression. To elucidate the activity of neuromediators on cytok ine secretion by glial cells, we studied the secretion of interleukin- 6 (IL-6) by cultured rat astrocytes after incubation with various neur otransmitters and neuropeptides. Norepinephrine (NE) and the beta-adre nergic agonist isoproterenol (IPT) induced IL-6 secretion in a dose-de pendent fashion. NE effect was predominantly mediated by beta2-adrener gic receptors with a minor contribution of alpha1-adrenergic receptors . The induction of IL-6 release by dibutyryl-cAMP indicated that IL-6 secretion secondary to beta2-adrenergic receptor activation probably o ccurs through cAMP signalling pathways. Vasoactive intestinal peptide (VIP) was the sole neuropeptide able to induce IL-6 secretion. NE and VIP promoted IL-6 mRNA synthesis and both substances synergized with i nterleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in inducing IL-6 release. Our findings provide further evidence that neurons modulate astrocyte cytokine production and thereby regulate ce ntral nervous system immune functions.