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ToxSci Advance Access originally published online on December 15, 2004
Toxicological Sciences 2005 84(1):139-148; doi:10.1093/toxsci/kfi055
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Toxicological Sciences vol. 84 no. 1 © Society of Toxicology 2005; all rights reserved.

Manganese Potentiates In Vitro Production of Proinflammatory Cytokines and Nitric Oxide by Microglia Through a Nuclear Factor kappa B–Dependent Mechanism

Nikolay M. Filipov*,{dagger},1, Richard F. Seegal* and David A. Lawrence*

* Wadsworth Center, New York State Department of Health; Albany, New York 11201; {dagger} Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State, Mississippi 39762

Received September 20, 2004; accepted November 24, 2004

Recent evidence suggests that the mechanism of manganese (Mn) neurotoxicity involves activation of microglia and/or astrocytes; as a consequence, neurons adjacent to the activated microglia may be injured. Mn modulation of proinflammatory cytokine expression by microglia has not been investigated. Therefore, the objectives of this research were to (1) assess whether Mn induces proinflammatory cytokine expression and/or modulates lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines and (2) investigate possible mechanisms for such an induction. N9 microglia were exposed in vitro to increasing concentrations (50–1000 µM) of Mn in the presence or absence of LPS (10, 100, or 500 ng/ml). After various incubation times (up to 48 h), media levels of several cytokines and nitric oxide (NO) were determined, as was the expression of the inducible form of NO synthase (iNOS). Lactate dehydrogenase (LDH) release into the medium and the cellular uptake of Neutral Red were used as general measures for cytotoxicity. In the absence of LPS, Mn moderately increased interleukin-6 and tumor necrosis factor alpha (TNF-a) production only at higher Mn concentrations, which were cytotoxic. At all LPS doses, however, proinflammatory cytokine production was dose-dependently increased by Mn. Similarly, LPS-induced NO production and iNOS expression were substantially enhanced by Mn. Pharmacological manipulations indicated that nuclear factor kappa B (NF{kappa}B) activation is critical for the observed enhancement of cytokine and NO production. Within the context of inflammation, increased production of proinflammatory cytokines and NO by Mn could be an important part of the mechanism by which Mn exerts its neurotoxicity.

Key Words: manganese; microglia; neurotoxicity; inflammation; cytokines; nitric oxide.


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