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Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: role in controlling microglial hydrogen peroxide and inflammatory cytokine output.

ABSTRACT: Excessive manganese (Mn) exposure increases output of glial-derived inflammatory products, which may indirectly contribute to the neurotoxic effects of this essential metal. In microglia, Mn increases hydrogen peroxide (H(2)O(2)) release and potentiates lipopolysaccharide (LPS)-induced cytokines (TNF-?, IL-6) and nitric oxide (NO). Inducible heme-oxygenase (HO-1) plays a role in the regulation of inflammation and its expression is upregulated in response to oxidative stressors, including metals and LPS. Because Mn can oxidatively affect neurons both directly and indirectly, we investigated the effect of Mn exposure on the induction of HO-1 in resting and LPS-activated microglia (N9) and dopaminergic neurons (N27). In microglia, 24h exposure to Mn (up to 250 ?M) had minimal effects on its own, but it markedly potentiated LPS (100 ng/ml)-induced HO-1 protein and mRNA. Inhibition of microglial HO-1 activity with two different inhibitors indicated that HO-1 is a positive regulator of the Mn-potentiated cytokine output and a negative regulator of the Mn-induced H(2)O(2) output. Mn enhancement of LPS-induced HO-1 does not appear to be dependent on H(2)O(2) or NO, as Mn+LPS-induced H(2)O(2) release was not greater than the increase induced by Mn alone and inhibition of iNOS did not change Mn potentiation of HO-1. However, because Mn exposure potentiated the LPS-induced nuclear expression of small Maf proteins, this may be one mechanism Mn uses to affect the expression of HO-1 in activated microglia. Finally, the potentiating effects of Mn on HO-1 appear to be glia-specific for Mn, LPS, or Mn+LPS did not induce HO-1 in N27 neuronal cells.

SUBMITTER: Dodd CA

PROVIDER: S-EPMC3253657 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: role in controlling microglial hydrogen peroxide and inflammatory cytokine output.

Dodd Celia A CA Filipov Nikolay M NM

Neurotoxicology 20110925 6

Excessive manganese (Mn) exposure increases output of glial-derived inflammatory products, which may indirectly contribute to the neurotoxic effects of this essential metal. In microglia, Mn increases hydrogen peroxide (H(2)O(2)) release and potentiates lipopolysaccharide (LPS)-induced cytokines (TNF-α, IL-6) and nitric oxide (NO). Inducible heme-oxygenase (HO-1) plays a role in the regulation of inflammation and its expression is upregulated in response to oxidative stressors, including metals ...[more]

PMID: 21963524

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Project description:Heme oxygenase-1 (HO-1) can exert anti-inflammatory and antioxidant effects. Acute lung injury (ALI) is associated with increased inflammation and influx of proinflammatory cells and mediators in the airspaces and lung parenchyma. In this study, we demonstrate that pterostilbene 4'-?-glucoside (4-PG), the glycosylated form of the antioxidant pterostilbene (PTER), can protect against lipopolysaccharide- (LPS-) or Pseudomonas aeruginosa- (P. aeruginosa-) induced ALI when applied as a pretreatment or therapeutic post-treatment, via the induction of HO-1. To determine whether HO-1 mediates the antioxidant and anti-inflammatory effects of 4-PG, we subjected mice genetically deficient in Hmox-1 to LPS-induced ALI and evaluated histological changes, HO-1 expression, and proinflammatory cytokine levels in bronchoalveolar lavage (BAL) fluid. 4-PG exhibited protective effects on LPS- or P. aeruginosa-induced ALI by ameliorating pathological changes in lung tissue and decreasing proinflammatory cytokines. In addition, HO-1 expression was significantly increased by 4-PG in cells and in mouse lung tissues. The glycosylated form of pterostilbene (4-PG) was more effective than PTER in inducing HO-1 expression. Genetic deletion of Hmox-1 abolished the protective effects of 4-PG against LPS-induced inflammatory responses. Furthermore, we found that 4-PG decreased both intracellular ROS levels and mitochondrial (mt) ROS production in a manner dependent on HO-1. Pharmacological application of the HO-1 reaction product carbon monoxide (CO), but not biliverdin or iron, conferred protection in Hmox-1-deficient macrophages. Taken together, these results demonstrate that 4-PG can increase HO-1 expression, which plays a critical role in ameliorating intracellular and mitochondrial ROS production, as well as in downregulating inflammatory responses induced by LPS. Therefore, these findings strongly suggest that HO-1 mediates the antioxidant and anti-inflammatory effects of 4-PG.

Dataset Information

Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: role in controlling microglial hydrogen peroxide and inflammatory cytokine output.

Publications

Manganese potentiates LPS-induced heme-oxygenase 1 in microglia but not dopaminergic cells: role in controlling microglial hydrogen peroxide and inflammatory cytokine output.

Similar Datasets

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