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p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils

Maria Alvarado-Kristensson1, Fredrik Melander, Karin Leandersson

  • 1Division of Experimental Pathology, Lund University, U-MAS, Entrance 78, Floor 3, SE-205 02 Malmö, Sweden. maria.alvarado-kristensson@exppat.mas.lu.se

The Journal of Experimental Medicine
|February 19, 2004
PubMed

Insights

p38-mitogen-activated protein kinase (MAPK) directly inhibits neutrophil apoptosis by phosphorylating caspases-8 and -3. This finding reveals a novel mechanism regulating inflammatory processes and cell death.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Neutrophil apoptosis is crucial for resolving inflammation.
  • p38-MAPK signaling is typically a survival pathway in neutrophils.

Purpose of the Study:

  • To investigate the role of p38-MAPK in neutrophil apoptosis.
  • To elucidate the molecular mechanisms linking p38-MAPK to caspase activity.

Main Methods:

  • Immunoprecipitation to detect protein interactions.
  • In vitro kinase assays to assess p38-MAPK activity.
  • Phosphopeptide mapping to identify phosphorylation sites.
  • Mutational analysis of caspase-3 activity.

Main Results:

  • p38-MAPK associates with and phosphorylates caspase-8 and caspase-3.
  • This phosphorylation inhibits caspase activity at specific serine residues (Ser364 for caspase-8, Ser150 for caspase-3).
  • Mutating caspase-3 at Ser150 rendered neutrophils resistant to p38-MAPK inhibition during apoptosis.

Conclusions:

  • p38-MAPK directly inhibits neutrophil apoptosis by inactivating caspases-8 and -3.
  • This mechanism provides a novel way p38-MAPK regulates inflammatory responses.
  • Targeting this pathway could offer new therapeutic strategies for inflammatory diseases.

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