LPS-induced release of IL-6 from glia modulates production of IL-1β in a JAK2-dependent manner

Background: compelling evidence has implicated neuroinflammation in the pathogenesis of a number of neurodegenerative conditions. chronic activation of both astrocytes and microglia leads to excessive secretion of proinflammatory molecules such as tnfα,il-6 and il-1β with potentially deleterious consequences for neuronal viability. many signaling pathways involving the mitogen-activated protein kinases (mapks),nuclear factor κb (nfκb) complex and the janus kinases (jaks)/signal transducers and activators of transcription (stat)-1 have been implicated in the secretion of proinflammatory cytokines from glia. we sought to identify signaling kinases responsible for cytokine production and to delineate the complex interactions which govern time-related responses to lipopolysaccharide (lps).methods: we examined the time-related changes in certain signaling events and the release of proinflammatory cytokines from lps-stimulated co-cultures of astrocytes and microglia isolated from neonatal rats.results: tnfα was detected in the supernatant approximately 1 to 2 hours after lps treatment while il-1β and il-6 were detected after 2 to 3 and 4 to 6 hours,respectively. interestingly,activation of nfκb signaling preceded release of all cytokines while phosphorylation of stat1 was evident only after 2 hours,indicating that activation of jak/stat may be important in the up-regulation of il-6 production. additionally,incubation of glia with tnfα induced both phosphorylation of jak2 and stat1 and the interaction of jak2 with the tnfα receptor (tnfr1). co-treatment of glia with lps and recombinant il-6 protein attenuated the lps-induced release of both tnfα and il-1β while potentiating the effect of lps on suppressor of cytokine signaling (socs)3 expression and il-10 release.conclusions: these data indicate that tnfα may regulate il-6 production through activation of jak/stat signaling and that the subsequent production of il-6 may impact on the release of tnfα,il-1β and il-10. © 2012 minogue et al.; licensee biomed central ltd.