Abstract
BackgroundAstrocytes are responsible for a broad range of functions that maintain homeostasis in the brain. However, their response to the pro-inflammatory cytokines released by activated microglia in various neurological pathologies may exacerbate neurodegenerative processes. Accumulating evidence suggests that omega-3 docosahexaenoic fatty acid (DHA) has an anti-inflammatory effect in various cell cultures studies and in a variety of neurological disorders. In this study we examined the mechanism involved in the inhibition of the pro-inflammatory response by DHA in astrocytes treated with IL-1β.Methods and resultsActivation of the transcription factors NF-κB and AP-1 was measured in IL-1β-treated primary astrocytes incubated with various concentrations of DHA. COX-2 and iNOS protein expression was determined by Western blot, and TNF-α and IL-6 secretion was measured using ELISA-based assays. DHA treatment inhibited translocation of p65NF-κB to the nucleus, significantly lowered p65NF-κB protein level and fluorescence of p65NF-κB in the nucleus, reduced dose-dependently IκB protein phosphorylation, and the binding of the AP-1 transcription factor members (c-Jun/c-Fos) to the specific TPA-response element (TRE) of DNA. In addition, the expression of pro-inflammatory COX-2 and iNOS proteins was downregulated and TNF-α and IL-6 secretion was also reduced.ConclusionsThese results indicate that DHA is a powerful factor that reduces the pro-inflammatory response in astrocytes. Consequently, successful introduction of DHA into the astrocyte membranes can attenuate neuroinflammation, which is a key factor of age-related neurodegenerative disorders.
Highlights
Astrocytes are responsible for a broad range of functions that maintain homeostasis in the brain
Since oxidative stress is a powerful factor of NF-κB activation [12] and cross-talk has been reported between the nuclear factor erythroid-2-related factor 2 (Nrf2) and NF-κB pathways [13, 14], in the present study we examined whether docosahexaenoic fatty acid (DHA) can inhibit NF-κB activation and a pro-inflammatory response in astrocytes
Our previous findings indicate that p38 mitogenactivated protein kinase (p38 MAPK) is involved in the Nrf2-dependent anti-oxidative enzyme expression in DHA-enriched astrocytes [11], so in the present study we examined activation of activator protein 1 (AP-1) transcription factor members that can be phosphorylated by MAP kinases
Summary
Astrocytes are responsible for a broad range of functions that maintain homeostasis in the brain. Their response to the pro-inflammatory cytokines released by activated microglia in various neurologi‐ cal pathologies may exacerbate neurodegenerative processes. Accumulating evidence suggests that omega-3 docosahexaenoic fatty acid (DHA) has an anti-inflammatory effect in various cell cultures studies and in a variety of neurological disorders. Reactive astrocytes display upregulation of the complement cascade genes [6] and an enhanced release of proinflammatory cytokines, such as IL-1β and TNF-α [7], which are destructive to synapses [8] and can be a feature of chronic pain pathologies [9]. In the canonical activation of the NF-κB heterodimer, the IκB inhibitor is phosphorylated by IκB kinase (IKK) following activation by tumor necrosis factor receptor (TNF-R)-associated factors (TRAFs) that bind to the cytoplasmic regions of variety receptors, e.g. the IL-1/TLR superfamily of receptors [10]
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