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Manganese-induced NF-kappaB activation and nitrosative stress is decreased by estrogen in juvenile mice.

ABSTRACT: Manganese toxicity can cause a neurodegenerative disorder affecting cortical and basal ganglia structures with a neurological presentation resembling features of Parkinson's disease. Children are more sensitive to Mn-induced neurological dysfunction than adults, and recent studies from our laboratory revealed a marked sensitivity of male juvenile mice to neuroinflammatory injury from Mn, relative to females. To determine the role of estrogen (E2) in mediating sex-dependent vulnerability to Mn-induced neurotoxicity, we exposed transgenic mice expressing an NF-?B-driven enhanced green fluorescent protein (EGFP) reporter construct (NF-?B-EGFP mice) to Mn, postulating that supplementing male mice with E2 during juvenile development would attenuate neuroinflammatory changes associated with glial activation, including expression of inducible nitric oxide synthase (NOS2) and neuronal protein nitration. Juvenile NF-?B-EGFP mice were separated in groups composed of females, males, and males surgically implanted with Silastic capsules containing 25 ?g of 17-?-estradiol (E2) or vehicle control. Mice were then treated with 0 or 100 mg/Kg MnCl(2) by intragastric gavage from postnatal days 21-34. Manganese treatment caused alterations in levels of striatal dopamine, as well as increases in NF-?B reporter activity and NOS2 expression in both microglia and astrocytes that were prevented by supplementation with E2. E2 also decreased neuronal protein nitration in Mn-treated mice and inhibited apoptosis in striatal neurons cocultured with Mn-treated astrocytes in vitro. These data indicate that E2 protects against Mn-induced neuroinflammation in developing mice and that NF-?B is an important regulator of neuroinflammatory gene expression in glia associated with nitrosative stress in the basal ganglia during Mn exposure.

SUBMITTER: Moreno JA

PROVIDER: S-EPMC3143469 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Manganese-induced NF-kappaB activation and nitrosative stress is decreased by estrogen in juvenile mice.

Moreno Julie A JA Streifel Karin M KM Sullivan Kelly A KA Hanneman William H WH Tjalkens Ronald B RB

Toxicological sciences : an official journal of the Society of Toxicology 20110421 1

Manganese toxicity can cause a neurodegenerative disorder affecting cortical and basal ganglia structures with a neurological presentation resembling features of Parkinson's disease. Children are more sensitive to Mn-induced neurological dysfunction than adults, and recent studies from our laboratory revealed a marked sensitivity of male juvenile mice to neuroinflammatory injury from Mn, relative to females. To determine the role of estrogen (E2) in mediating sex-dependent vulnerability to Mn-in ...[more]

PMID: 21512103

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Project description:BackgroundSilicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFalpha) plays a central role in the pathogenesis of silicosis. TNFalpha signaling is mediated by the transcription factor, Nuclear Factor (NF)-kappaB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-kappaB activation represents a potential therapeutic strategy for silicosis.Methods/findingsIn the present work we evaluated the lung transplant database (May 1986-July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFalpha expressing macrophage and NF-kappaB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16-7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8-15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22-0.9 yr) following lung transplantation (2.4 yr; CI:1.5-3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-kappaB activation with a pharmacologic inhibitor (BAY 11-7085) of IkappaB alpha phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IkappaB alpha mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica.ConclusionsAlthough limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-kappaB protects from silica-induced lung injury, epithelial cell specific NF-kappaB inhibition appears to aggravate the outcome of experimental silicosis.

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Manganese-induced NF-kappaB activation and nitrosative stress is decreased by estrogen in juvenile mice.

Publications

Manganese-induced NF-kappaB activation and nitrosative stress is decreased by estrogen in juvenile mice.

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