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p38 MAPK and MSK1 mediate caspase-8 activation in manganese-induced mitochondria-dependent cell death

B El Mchichi1, A Hadji, A Vazquez

  • 1INSERM, UMR 542, Université Paris-Sud, Hôpital Paul Brousse, 14 avenue Paul Vaillant Couturier, 94807 Villejuif, France.

Cell Death and Differentiation
|June 23, 2007
PubMed

Insights

Manganese (Mn2+) induces apoptosis in human B cells via a pathway involving caspase-8, p38 MAPK, and MSK1. This study clarifies the molecular mechanisms of manganese-induced cell death.

Area of Science:

  • Cell Biology
  • Toxicology
  • Immunology

Background:

  • Heavy metals regulate cell apoptosis, with manganese (Mn2+) being a potent inducer.
  • The precise mechanisms of Mn2+-induced apoptosis are not fully understood, particularly in human B cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying manganese (Mn2+)-induced apoptosis in human B cells.
  • To identify the specific signaling pathways involved in Mn2+-triggered cell death.

Main Methods:

  • Utilized short hairpin RNAs (shRNAs) targeting caspase-8 to assess its role in Mn2+-induced apoptosis.
  • Employed pharmacological inhibitors and dominant-negative mutants to investigate the involvement of p38 MAPK and MSK1.
  • Analyzed caspase-3 and caspase-8 activation, mitochondrial activation, and protein phosphorylation.

Main Results:

  • Mn2+-induced apoptosis in human B cells involves caspase-8-dependent mitochondrial activation and subsequent caspase-3 activity.
  • Caspase-8 activation is regulated by a pathway independent of FADD, involving sequential activation of p38 MAPK and MSK1.
  • Inhibition of p38 MAPK or MSK1 blocked Mn2+-induced caspase-8 activation, confirming their sequential roles.

Conclusions:

  • Mn2+-induced apoptosis in human B cells proceeds through a novel pathway: p38 MAPK -> MSK1 -> caspase-8 -> mitochondria.
  • This research provides a detailed model for caspase-8 regulation during heavy metal-induced apoptosis.
  • Understanding these mechanisms may inform strategies for managing heavy metal toxicity in B cell-related conditions.

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