Document Detail

Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells.
MedLine Citation:
PMID:  20589745     Owner:  NLM     Status:  MEDLINE    
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.
Patrick L Crittenden; Nikolay M Filipov
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of applied toxicology : JAT     Volume:  31     ISSN:  1099-1263     ISO Abbreviation:  J Appl Toxicol     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-24     Completed Date:  2011-04-07     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8109495     Medline TA:  J Appl Toxicol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1-10     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 John Wiley & Sons, Ltd.
Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762, USA.
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MeSH Terms
Cell Line
Cyclooxygenase 2 / metabolism
Interleukin-6 / metabolism
JNK Mitogen-Activated Protein Kinases / metabolism
Lipopolysaccharides / metabolism
Manganese / toxicity*
Microglia / cytology*
Mitogen-Activated Protein Kinase Kinases / metabolism*
Signal Transduction
Tumor Necrosis Factor-alpha / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism
Grant Support
Reg. No./Substance:
0/Interleukin-6; 0/Lipopolysaccharides; 0/Tumor Necrosis Factor-alpha; 7439-96-5/Manganese; EC 1.14.99.-/Ptgs2 protein, mouse; EC 2; EC Mitogen-Activated Protein Kinases; EC Mitogen-Activated Protein Kinases; EC Protein Kinase Kinases

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