Abstract
BackgroundInflammatory responses in the CNS mediated by activated glial cells play an important role in host-defense but are also involved in the development of neurodegenerative diseases. Resveratrol is a natural polyphenolic compound that has cardioprotective, anticancer and anti-inflammatory properties. We investigated the capacity of resveratrol to protect microglia and astrocyte from inflammatory insults and explored mechanisms underlying different inhibitory effects of resveratrol on microglia and astrocytes.MethodsA murine microglia cell line (N9), primary microglia, or astrocytes were stimulated by LPS with or without different concentrations of resveratrol. The expression and release of proinflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1) and iNOS/NO by the cells were measured by PCR/real-time PCR and ELISA, respectively. The phosphorylation of the MAP kinase superfamily was analyzed by western blotting, and activation of NF-κB and AP-1 was measured by luciferase reporter assay and/or electrophoretic mobility shift assay.ResultsWe found that LPS stimulated the expression of TNF-α, IL-1β, IL-6, MCP-1 and iNOS in murine microglia and astrocytes in which MAP kinases, NF-κB and AP-1 were differentially involved. Resveratrol inhibited LPS-induced expression and release of TNF-α, IL-6, MCP-1, and iNOS/NO in both cell types with more potency in microglia, and inhibited LPS-induced expression of IL-1β in microglia but not astrocytes. Resveratrol had no effect on LPS-stimulated phosphorylation of ERK1/2 and p38 in microglia and astrocytes, but slightly inhibited LPS-stimulated phosphorylation of JNK in astrocytes. Resveratrol inhibited LPS-induced NF-κB activation in both cell types, but inhibited AP-1 activation only in microglia.ConclusionThese results suggest that murine microglia and astrocytes produce proinflammatory cytokines and NO in response to LPS in a similar pattern with some differences in signaling molecules involved, and further suggest that resveratrol exerts anti-inflammatory effects in microglia and astrocytes by inhibiting different proinflammatory cytokines and key signaling molecules.
Highlights
Inflammatory responses in the CNS mediated by activated glial cells play an important role in hostdefense but are involved in the development of neurodegenerative diseases
We used inhibitors for MAP kinases and transcription factors to determine whether activation of ERK1/2, p38, jun N-terminal kinase (JNK), NF-B, or AP-1 contribute to the induction of proinflammatory cytokines and iNOS expression by LPS in microglia and astrocytes
While PD98059, SP600125, and curcumin inhibited MCP-1 and iNOS expression in both microglia and astrocytes, SB203580 inhibited MCP-1 and iNOS expression only in astrocytes, and sulfasalazine inhibited iNOS but not MCP-1 in both cell types, suggesting that ERK1/2, JNK and AP-1 are involved in LPS-induced expression of MCP-1 and iNOS in microglia and astrocytes, that p38 is involved in LPS-induced expression of MCP-1 and iNOS in astrocytes but not microglia, and that NF-B is involved in LPS-induced expression of iNOS but not MCP-1 in both cell types
Summary
Inflammatory responses in the CNS mediated by activated glial cells play an important role in hostdefense but are involved in the development of neurodegenerative diseases. Astrocytes are the main glial cell type in the brain involved in maintaining CNS homeostasis. They respond promptly to injury and regulate neuroinflammatory events [2,3,4]. Both in vitro and in vivo studies have documented the ability of astrocytes to produce a variety of cytokines, including IL-1, IL-6, IL-10, interferon-a (INF-a), IFN-b, TNF-a, TNF-b; and chemokines, including RANTES (CCL5), IL-8 (CXCL8) and MCP-1 [3]. Limiting inflammatory cytokine production by activated microglia and astrocytes should be beneficial for prevention of neuroinflammation and neurodegeneration
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