Abstract
BackgroundGlia are key regulators of inflammatory responses within the central nervous system (CNS) following infection or trauma. We have previously demonstrated the ability of activated glia to rapidly produce pro-inflammatory mediators followed by a transition to an anti-inflammatory cytokine production profile that includes the immunosuppressive cytokine interleukin (IL)-10 and the closely related cytokine IL-19. IL-24, another member of the IL-10 family, has been studied in a number of inflammatory conditions in the periphery and is known to modulate immune cell activity. However, the ability of glia to produce IL-24 remains unclear and the effects of this pleiotropic cytokine on glial immune functions have not been investigated.MethodsIn this study, we have assessed whether primary murine glia produce IL-24 following stimulation and evaluated the effect of this cytokine on the immune responses of such cells. We have utilized RT-PCR and immunoblot analyses to assess the expression of IL-24 and its cognate receptors by astrocytes following challenge with bacteria or their components. Furthermore, we have determined the effect of recombinant IL-24 on astrocyte immune signaling and responses to clinically relevant bacteria using RT-PCR and specific capture ELISAs.ResultsWe demonstrate that astrocytes express IL-24 mRNA and release detectable amounts of this cytokine protein in a delayed manner following bacterial challenge. In addition, we have determined that glia constitutively express the cognate receptors for IL-24 and show that such expression can be increased in astrocytes following activation. Importantly, our results indicate that IL-24 exerts an immunosuppressive effect on astrocytes by elevating suppressor of cytokine signaling 3 expression and limiting IL-6 production following challenge. Furthermore, we have demonstrated that IL-24 can also augment the release of IL-10 by bacterially challenged astrocytes and can induce the expression of the potentially neuroprotective mediators, glutamate transporter 1, and cyclooxygenase 2.ConclusionsThe expression of IL-24 and its cognate receptors by astrocytes following bacterial challenge, and the ability of this cytokine to limit inflammatory responses while promoting the expression of immunosuppressive and/or neuroprotective mediators, raises the intriguing possibility that IL-24 functions to regulate or resolve CNS inflammation following bacterial infection in order to limit neuronal damage.
Highlights
Glia are key regulators of inflammatory responses within the central nervous system (CNS) following infection or trauma
IL-24 is expressed by murine glial cells following bacterial stimulation To begin to assess whether cells within the CNS can express IL-24, we have determined whether Messenger ribonucleic acid (mRNA) encoding IL-24 is present in the CNS either constitutively or following bacterial infection
To determine whether the presence of IL-24 mRNA in the brain following in vivo infection is due to the expression of this cytokine by glial cells, we have assessed the in vitro IL-24 expression in isolated primary murine astrocytes and microglia by semi-quantitative and quantitative real-time reverse transcription PCR (RT-PCR)
Summary
Glia are key regulators of inflammatory responses within the central nervous system (CNS) following infection or trauma. Glial cells rapidly respond to invading pathogens by the production of an array of inflammatory mediators that include chemokines and cytokines Such responses influence the integrity of the blood–brain barrier and serve to recruit leukocytes and activate them upon arrival at the site of infection [1, 2]. To limit the detrimental effects of inflammation, cell responses transition to a resolving phenotype that is typically characterized by a change in the cytokine production profile [3,4,5,6] At peripheral sites, such compensatory anti-inflammatory responses are associated with the production of key immunosuppressive cytokines including IL-10 [7], and elevations in the level of this cytokine accompany host protection following bacterial or viral infection of the CNS [8, 9]. We have previously demonstrated that both microglia and astrocytes show delayed expression of IL-10 following challenge with clinically relevant bacterial pathogens that functions to limit the inflammatory responses of these cells [10]
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