OVEREXPRESSION OF INTERLEUKIN-6 IN THE CENTRAL-NERVOUS-SYSTEM OF TRANSGENIC MICE INCREASES CENTRAL BUT NOT SYSTEMIC PROINFLAMMATORY CYTOKINE PRODUCTION

Production of inflammatory cytokines, including tumor necrosis factor (TNF), interleukin-l (IL-I) and interleukin-6 (IL-6), in the brain is increased in various diseases. To investigate the relationships betwee n the effect of overproduction of IL-6 in the brain on central and per ipheral production of TNF, IL-1 beta and n-6 itself, we used transgeni c mice (NSE-hIL-6) where neuronal human IL-6 expression under the cont rol of the neuronal specific enolase promoter results in astrocytosis and gliosis. These mice had higher cerebral endogenous IL-6(12-fold), IL-1 beta(12-fold) and TNF(4-fold) production measured in brain homoge nates after intracerebroventricular (i.c.v.) injection of 2.5 mu g LPS , lipopolysaccharide (LPS) than wild-type mice (no TNF or IL-1 were de tectable in saline-injected NSE or control mice). Cerebral cytokines p roduction was also increased in NSE-hIL-6 mice treated i.p. with LPS d oses that do not normally induce cytokines in the brain. The induction of peripheral (serum or spleen) TNF, IL-IP or IL-6 was the same in al l these experiments in NSE-hIL-6 and wild-type mice. Furthermore, usin g microglial cell clone pretreated in vitro with n-6, we noted an incr ease in LPS-induced TNF and IL-6 production and proliferation of pretr eated cells than control. This study indicates that overproduction of IL-6 in the central nervous system (CNS) may ultimately result in incr eased central production of inflammatory cytokines, probably due to in creased proliferation and activation of the cells which produce cytoki ne in the CNS.