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Lipopolysaccharide induces anandamide synthesis in macrophages via CD14/MAPK/phosphoinositide 3-kinase/NF-kappa B independently of platelet-activating factor

Academic Article
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Overview

authors

  • Liu, J.
  • Batkai, S.
  • Pacher, P.
  • Harvey-White, J.
  • Wagner, J. A.
  • Cravatt, Benjamin
  • Gao, B.
  • Kunos, G.

publication date

  • November 2003

journal

  • Journal of Biological Chemistry  Journal

abstract

  • Macrophage-derived endocannabinoids have been implicated in endotoxin (lipopolysaccharide (LPS))-induced hypotension, but the endocannabinoid involved and the mechanism of its regulation by LPS are unknown. In RAW264.7 mouse macrophages, LPS (10 ng/ml) increases anandamide (AEA) levels >10-fold via CD14-, NF-kappaB-, and p44/42-dependent, platelet-activating factor-independent activation of the AEA biosynthetic enzymes, N-acyltransferase and phospholipase D. LPS also induces the AEA-degrading enzyme fatty acid amidohydrolase (FAAH), and inhibition of FAAH activity potentiates, whereas actinomycin D or cycloheximide blocks the LPS-induced increase in AEA levels and N-acyltransferase and phospholipase D activities. In contrast, cellular levels of the endocannabinoid 2-arachidonoylglycerol (2-AG) are unaffected by LPS but increased by platelet-activating factor. LPS similarly induces AEA, but not 2-AG, in mouse peritoneal macrophages where basal AEA levels are higher, and the LPS-stimulated increase in AEA is potentiated in cells from FAAH-/- as compared with FAAH+/+ mice. Intravenous administration of 107 LPS-treated mouse macrophages to anesthetized rats elicits hypotension, which is much greater in response to FAAH-/- than FAAH+/+ cells and is susceptible to inhibition by SR141716, a cannabinoid CB1 receptor antagonist. We conclude that AEA and 2-AG synthesis are differentially regulated in macrophages, and AEA rather than 2-AG is a major contributor to LPS-induced hypotension.

subject areas

  • Acyltransferases
  • Amidohydrolases
  • Animals
  • Antigens, CD14
  • Arachidonic Acids
  • Cell Line
  • Endocannabinoids
  • Glycerides
  • Hypotension
  • Kinetics
  • Lipopolysaccharides
  • Macrophages
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • NF-kappa B
  • Phosphatidylethanolamines
  • Phosphatidylinositol 3-Kinases
  • Phospholipase D
  • Platelet Activating Factor
  • Polyunsaturated Alkamides
  • Rats
  • Rats, Sprague-Dawley
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M306062200

PubMed ID

  • 12949078
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Additional Document Info

start page

  • 45034

end page

  • 45039

volume

  • 278

issue

  • 45

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