Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils

J Clin Invest. 1999 Mar;103(6):851-8. doi: 10.1172/JCI5257.

Abstract

Activation of leukocytes by proinflammatory stimuli selectively initiates intracellular signal transduction via sequential phosphorylation of kinases. Lipopolysaccharide (LPS) stimulation of human neutrophils is known to result in activation of p38 mitogen-activated protein kinase (MAPk); however, the upstream activator(s) of p38 MAPk is unknown, and consequences of p38 MAPk activation remain largely undefined. We investigated the MAPk kinase (MKK) that activates p38 MAPk in response to LPS, the p38 MAPk isoforms that are activated as part of this pathway, and the functional responses affected by p38 MAPk activation. Although MKK3, MKK4, and MKK6 all activated p38 MAPk in experimental models, only MKK3 was found to activate recombinant p38 MAPk in LPS-treated neutrophils. Of p38 MAPk isoforms studied, only p38alpha and p38delta were detected in neutrophils. LPS stimulation selectively activated p38alpha. Specific inhibitors of p38alpha MAPk blocked LPS-induced adhesion, nuclear factor-kappa B (NF-kappaB) activation, and synthesis of tumor necrosis factor-alpha (TNF-alpha). Inhibition of p38alpha MAPk resulted in a transient decrease in TNF-alpha mRNA accumulation but persistent loss of TNF-alpha synthesis. These findings support a pathway by which LPS stimulation of neutrophils results in activation of MKK3, which in turn activates p38alpha MAPk, ultimately regulating adhesion, NF-kappaB activation, enhanced gene expression of TNF-alpha, and regulation of TNF-alpha synthesis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Adhesion
  • Down-Regulation
  • Enzyme Activation / drug effects
  • Humans
  • Isoenzymes / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / pharmacology*
  • MAP Kinase Kinase 3
  • Mitogen-Activated Protein Kinase Kinases*
  • Mitogen-Activated Protein Kinases*
  • Models, Biological
  • NF-kappa B / metabolism
  • Neutrophils / drug effects*
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / biosynthesis
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Isoenzymes
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP2K3 protein, human
  • Mitogen-Activated Protein Kinase Kinases