| Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells. | |
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MedLine Citation:
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PMID: 20589745 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Multiple studies demonstrate that manganese (Mn) exposure potentiates inflammatory mediator output from activated glia; this increased output is associated with enhanced mitogen activated protein kinase (MAPK: p38, ERK and JNK) activity. We hypothesized that Mn activates MAPK by activating the kinases upstream of MAPK, i.e. MKK-3/6, MKK-1/2 and MKK-4 (responsible for activation of p38, ERK, and JNK, respectively), and/or by inhibiting a major phosphatase responsible for MAPK inactivation, MKP-1. Exposure of N9 microglia to Mn (250 µm), LPS (100 ng ml⁻¹) or Mn + LPS increased MKK-3/6 and MKK-4 activity at 1 h; the effect of Mn + LPS on MKK-4 activation was greater than the rest. At 4 h, Mn, LPS, and Mn + LPS increased MKK-3/6 and MKK-1/2 phosphorylation, whereas MKK-4 was activated only by Mn and Mn + LPS. Besides activating MKK-4 via Ser257/Thr261 phosphorylation, Mn (4 h) prevented MKK-4's phosphorylation on Ser80, which negatively regulates MKK-4 activity. Exposure to Mn or Mn + LPS (1 h) decreased both mRNA and protein expression of MKP-1, the negative MAPK regulator. In addition, we observed that at 4 h, but not at 1 h, a time point coinciding with increased MAPK activity, Mn + LPS markedly increased TNF-α, IL-6 and Cox-2 mRNA, suggesting a delayed effect. The fact that all three major groups of MKKs, MKK-1/2, MKK-3/6 and MKK-4, are activated by Mn suggests that Mn-induced activation of MAPK occurs via traditional mechanisms, which perhaps involve the MAPKs furthest upstream, MKKKs (MAP3Ks). In addition, for all MKKs, Mn-induced activation was persistent at least for 4 h, indicating a long-term effect. |
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Authors:
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Patrick L Crittenden; Nikolay M Filipov |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Journal of applied toxicology : JAT Volume: 31 ISSN: 1099-1263 ISO Abbreviation: J Appl Toxicol Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-24 Completed Date: 2011-04-07 Revised Date: 2012-01-04 |
Medline Journal Info:
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Nlm Unique ID: 8109495 Medline TA: J Appl Toxicol Country: England |
Other Details:
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Languages: eng Pagination: 1-10 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 John Wiley & Sons, Ltd. |
Affiliation:
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Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cyclooxygenase 2 / metabolism Interleukin-6 / metabolism JNK Mitogen-Activated Protein Kinases / metabolism Lipopolysaccharides / metabolism Manganese / toxicity* Mice Microglia / cytology* Mitogen-Activated Protein Kinase Kinases / metabolism* Phosphorylation Signal Transduction Tumor Necrosis Factor-alpha / metabolism p38 Mitogen-Activated Protein Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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ES011654/ES/NIEHS NIH HHS; ES016965/ES/NIEHS NIH HHS; K22 ES011654-03/ES/NIEHS NIH HHS; R01 ES016965-01A1/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Interleukin-6; 0/Lipopolysaccharides; 0/Tumor Necrosis Factor-alpha; 7439-96-5/Manganese; EC 1.14.99.-/Ptgs2 protein, mouse; EC 1.14.99.1/Cyclooxygenase 2; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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