Lipopolysaccharide and platelet-activating factor stimulate expression of platelet-activating factor acetylhydrolase via distinct signaling pathways

Inflamm Res. 2011 Aug;60(8):735-44. doi: 10.1007/s00011-011-0326-5. Epub 2011 Mar 24.

Abstract

Objectives: This study was designed to investigate and characterize the ability of platelet-activating factor (PAF) to induce the expression of platelet-activating factor acetylhydrolase (PAF-AH).

Methods: Ribonuclease protection assays and quantitative real-time PCR were used to investigate the ability of lipopolysaccharide (LPS) and PAF to regulate PAF-AH mRNA expression in human monocyte-macrophage 6 (MM6) cells. Pharmacological inhibitors of mitogen activated protein kinases (MAPK) and PAF receptor antagonists were used to investigate the mechanism of regulation of PAF-AH.

Results: PAF-AH mRNA levels were increased upon exposure to LPS or PAF in a dose-dependent manner. LPS elicited a more potent and rapid increase in PAF-AH expression than the PAF-stimulated response. However, when administered concomitantly, PAF augmented the LPS-stimulated response. LPS-stimulated PAF-AH expression was susceptible to partial inhibition by a p38 MAPK inhibitor and PAF receptor antagonists. PAF-induced up-regulation of PAF-AH levels was solely mediated via the PAF receptor and was p38 MAPK-independent.

Conclusion: The proinflammatory mediators, LPS and PAF, increased levels of PAF-AH mRNA via distinct signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Azepines / metabolism
  • Cell Line / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / metabolism
  • Humans
  • Imidazoles / metabolism
  • Lipopolysaccharides / pharmacology*
  • MAP Kinase Signaling System / drug effects*
  • Platelet Activating Factor / antagonists & inhibitors
  • Platelet Activating Factor / pharmacology*
  • Platelet Membrane Glycoproteins / genetics
  • Platelet Membrane Glycoproteins / metabolism
  • Pyridines / metabolism
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Triazoles / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Azepines
  • Enzyme Inhibitors
  • Imidazoles
  • Lipopolysaccharides
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Pyridines
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Triazoles
  • platelet activating factor receptor
  • BN 50739
  • bepafant
  • p38 Mitogen-Activated Protein Kinases
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • SB 203580