Abstract
Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson’s disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation.
Highlights
Neuro-inflammatory process has been associated with most neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS) and Huntington’s disease [1]
The important pro-inflammatory mediators produced in response to LPS stimulation include tumor necrosis factor (TNF)-α, interleukin (IL)-1β, ROS (namely hydrogen peroxide(H2O2)), RNS (i.e., nitric oxide(NO)) that is induced by inducible nitric oxide synthase, and prostaglandin E2 that is induced by cyclooxygenase (COX)-2 [16,17,18]
Firstly we identify that LPS exerts a direct toxicity to neurons; secondly, we establish that IL-10 reduces LPS-induced neuronal loss in either the presence or the absence of glial cells; and lastly, we demonstrate that IL-10 inhibits LPS-induced glial activation by downregulation of pro-inflammatory mediators and upregulation of neurotrophic factors
Summary
Neuro-inflammatory process has been associated with most neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS) and Huntington’s disease [1]. Neuro-inflammation is characterized by the activation of brain glial cells, primarily microglia and astrocytes that release various soluble factors that include free radicals (reactive oxygen species (ROS) and reactive nitrogen species (RNS)), cytokines, and lipid metabolites [2] The majority of these glia-derived factors are pro-inflammatory and neurotoxic and are deleterious to oxidative damage-vulnerable nigral dopaminergic neurons [2]. Osmotic pump infusion of IL-10 into the substantia nigra protects against LPS-induced cell death of dopaminergic neurons, with a corresponding decrease in the number of activated microglia, suggesting that the reduction in microglia-mediated release of inflammatory mediators may contribute to the anti-inflammatory effect of IL-10 [30]. Our present study provides a new cue for IL-10 alleviation of PD neurodegeneration by its anti-inflammatory property
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