Manganese potentiates nuclear factor-kappaB-dependent expression of nitric oxide synthase 2 in astrocytes by activating soluble guanylate cyclase and extracellular responsive kinase signaling pathways

Document Type

Article

Abstract

Inflammatory activation of glial cells is associated with neuronal injury in several degenerative movement disorders of the basal ganglia, including manganese neurotoxicity. Manganese (Mn) potentiates the effects of inflammatory cytokines on nuclear factor-kappaB (NF-kappaB)-dependent expression of nitric oxide synthase 2 (NOS2) in astrocytes, but the signaling mechanisms underlying this effect have remained elusive. It was postulated in the present studies that direct stimulation of cGMP synthesis and activation of mitogen-activated protein (MAP) kinase signaling pathways underlies the capacity of Mn to augment NF-kappaB-dependent gene expression in astrocytes. Exposure of primary cortical astrocytes to a low concentration of Mn (10 microM) potentiated expression of NOS2 mRNA and protein along with production of NO in response to interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha), which was prevented by overexpression of dominant negative IkappaB alpha. Mn also potentiated IFNgamma- and TNFalpha-induced phosphorylation of extracellular response kinase (ERK), p38, and JNK, as well as cytokine-induced activation of a fluorescent NF-kappaB reporter construct in transgenic astrocytes. Activation of ERK preceded that of NF-kappaB and was required for maximal activation of NO synthesis. Independently of IFNgamma/TNFalpha, Mn-stimulated synthesis of cGMP in astrocytes and inhibition of soluble guanylate cyclase (sGC) abolished the potentiating effect of Mn on MAP kinase phosphorylation, NF-kappaB activation, and production of NO. These data indicate that near-physiological concentrations of Mn potentiate cytokine-induced expression of NOS2 and production of NO in astrocytes via activation of sGC, which promotes ERK-dependent enhancement of NF-kappaB signaling.

Medical Subject Headings

Animals; Animals, Newborn; Astrocytes (cytology, drug effects, enzymology, physiology); Culture Media; Cyclic GMP (metabolism); Enzyme Activation; Extracellular Signal-Regulated MAP Kinases (metabolism); Genes, Reporter; Guanylate Cyclase (metabolism); Manganese (pharmacology); Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B (physiology); Nitric Oxide (metabolism); Nitric Oxide Synthase Type II (genetics); RNA, Messenger (genetics); Signal Transduction (drug effects)

Publication Date

7-1-2008

Publication Title

Journal of neuroscience research

E-ISSN

1097-4547

Volume

86

Issue

9

First Page

2028

Last Page

38

PubMed ID

18335517

Digital Object Identifier (DOI)

10.1002/jnr.21640

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