Abstract
BackgroundCompelling 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).MethodsWe 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.ResultsTNFα 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.ConclusionsThese 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.
Highlights
Compelling evidence has implicated neuroinflammation in the pathogenesis of a number of neurodegenerative conditions
LPS induces activation of Janus kinase (JAK)/signal transducers and activators of transcription (STAT), mitogen-activated protein kinases (MAPK) and nuclear factor κB (NFκB) signaling pathways and proinflammatory cytokine secretion The expression and release of cytokines were examined in a time-dependent manner
IL-1β mRNA expression was increased at 1 h (P < 0.01; Student’s t-test for independent means; Figure 1C) and IL-1β release was increased at 3 h (P < 0.05; analysis of variance (ANOVA); Figure 1D)
Summary
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. Astrocytes provide structural, metabolic and trophic support for neurons [1] but they, like microglia, are immunocompetent cells capable of secreting inflammatory mediators. Chronic activation of both cell types leads to excessive secretion of proinflammatory molecules such as TNFα, IL-6 and IL-1β, an effect that may have deleterious consequences for neuronal viability. Astrogliosis and upregulation of TNFα, IL-1β and IL-6 expression have been reported in Alzheimer’s disease as well as Parkinson’s disease [2,3,4,5]
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