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 TNF α, IL-6 and IL-1 β with potentially deleterious consequences for neuronal viability. Many signaling pathways involving the mitogen-activated protein kinases (MAPKs), nuclear factor κ B (NF κ B) 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
TNF α was detected in the supernatant approximately 1 to 2 hours after LPS treatment while IL-1 β and IL-6 were detected after 2 to 3 and 4 to 6 hours, respectively. Interestingly, activation of NF κ B 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 TNF α induced both phosphorylation of JAK2 and STAT1 and the interaction of JAK2 with the TNF α receptor (TNFR1). Co-treatment of glia with LPS and recombinant IL-6 protein attenuated the LPS-induced release of both TNF α and IL-1 β while potentiating the effect of LPS on suppressor of cytokine signaling (SOCS)3 expression and IL-10 release.


CONCLUSIONS
These data indicate that TNF α 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 TNF α, IL-1 β and IL-10.
Trinity College Institute for Neuroscience, Lloyd building, University of Dublin, Trinity College, College Green, Dublin 2, Ireland. aminogu@tcd.ie
Aedín M
AM
Minogue
James P
JP
Barrett
Marina A
MA
Lynch
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D018920:Coculture Techniques; D050822:Cytokine Receptor gp130 / Q000378:metabolism* / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis*; D053614:Janus Kinase 2 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology
C494201:Il6st protein, rat; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130; C507927:Jak2 protein, rat; D053614:Janus Kinase 2