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Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen

Patrick L Crittenden1, Nikolay M Filipov

  • 1Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762, USA.

Journal of Applied Toxicology : JAT
|July 1, 2010
PubMed

Insights

Manganese exposure activates mitogen-activated protein kinases (MAPK) by affecting upstream kinases and inhibiting MKP-1. This persistent activation in microglia contributes to inflammatory responses, highlighting a long-term effect.

Area of Science:

  • Neuroimmunology
  • Toxicology
  • Cellular Signaling

Background:

  • Manganese (Mn) exposure is known to potentiate inflammatory mediator output from activated glia.
  • This inflammatory response is associated with enhanced mitogen-activated protein kinase (MAPK) activity, including p38, ERK, and JNK.

Purpose of the Study:

  • To investigate the hypothesis that Mn activates MAPK by modulating upstream kinases (MKK-3/6, MKK-1/2, MKK-4) and/or inhibiting the phosphatase MKP-1.
  • To elucidate the specific mechanisms and temporal effects of Mn exposure on MAPK signaling pathways in microglia.

Main Methods:

  • N9 microglia were exposed to Manganese (Mn), lipopolysaccharide (LPS), or a combination of Mn + LPS.
  • Activity of MKK kinases and phosphorylation of MKK-4 were measured at 1 and 4 hours.
  • mRNA and protein expression of MKP-1 were assessed, along with inflammatory markers TNF-α, IL-6, and Cox-2.

Main Results:

  • Mn, LPS, and Mn + LPS increased MKK-3/6 and MKK-4 activity at 1 hour, with Mn + LPS showing a greater effect on MKK-4.
  • At 4 hours, Mn, LPS, and Mn + LPS increased MKK-3/6 and MKK-1/2 phosphorylation, while MKK-4 was activated by Mn and Mn + LPS.
  • Mn exposure decreased MKP-1 expression and altered MKK-4 phosphorylation, leading to increased inflammatory gene expression (TNF-α, IL-6, Cox-2) at 4 hours.

Conclusions:

  • Mn activates MAPK signaling through traditional pathways involving MKK kinases and inhibition of MKP-1.
  • Mn-induced MAPK activation is persistent for at least 4 hours, suggesting a long-term effect on microglial inflammatory responses.
  • These findings provide mechanistic insights into Mn neurotoxicity and its role in neuroinflammation.

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