Astrocytes contribute to the immunocompetence of the central nervous system (CNS) via their expression of class II major histocompatibility complex (MHC) antigens and the production of inflammatory cytokines such as interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Of these cytokines, IL-6 is of particular interest because one of its many immune and inflammatory actions is the promotion of immunoglobulin synthesis, and it is thought that IL-6 expression within the brain exacerbates autoimmune diseases of the CNS, which are marked by local immunoglobulin production. Several stimuli induce astrocyte IL-6 expression, including such inducible endogenous factors as IL-1 beta and TNF-alpha. We have investigated the possibility that a constitutively present endogenous factor, the neurotransmitter norepinephrine (NE), can induce astrocyte IL-6 production. We report that NE induces both IL-6 mRNA and protein in primary neonatal rat astrocytes, with optimal induction at 10 microM. IL-6 protein induction by NE is comparable to that seen with IL-1 beta or TNF-alpha, and NE synergizes with these cytokines for a ten-fold enhanced effect. In contrast to astrocytes, microglia are relatively unresponsive to NE, IL-1 beta and TNF-alpha for IL-6 production. Experiments with the beta-adrenergic receptor agonist isoproterenol, and alpha and beta-adrenergic receptor antagonists (propranolol, phentolamine, atenolol, and yohimbine) indicate that beta 2 and alpha 1-adrenergic receptors are involved in NE induction of astrocyte IL-6 expression.(ABSTRACT TRUNCATED AT 250 WORDS)