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

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.

• Authors: Jie Liu, Sándor Batkai, Pál Pacher, Judith Harvey-White, Jens A Wagner, Benjamin F Cravatt, Bin Gao, George Kunos
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 45 Pg. 45034-9 (Nov 07 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12949078 (Publication Type: Journal Article)

Chemical References

• Arachidonic Acids
• Endocannabinoids
• Glycerides
• Lipopolysaccharide Receptors
• Lipopolysaccharides
• N-arachidonylphosphatidylethanolamine
• NF-kappa B
• Phosphatidylethanolamines
• Platelet Activating Factor
• Polyunsaturated Alkamides
• glyceryl 2-arachidonate
• Acyltransferases
• Phosphatidylinositol 3-Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases
• Phospholipase D
• Amidohydrolases
• fatty-acid amide hydrolase
• anandamide

Topics

• Acyltransferases (metabolism)
• Amidohydrolases (deficiency, genetics, physiology)
• Animals
• Arachidonic Acids (biosynthesis)
• Cell Line
• Endocannabinoids
• Glycerides (biosynthesis)
• Hypotension (etiology)
• Kinetics
• Lipopolysaccharide Receptors (physiology)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism, transplantation)
• Male
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3
• Mitogen-Activated Protein Kinases (metabolism)
• NF-kappa B (physiology)
• Phosphatidylethanolamines
• Phosphatidylinositol 3-Kinases (metabolism)
• Phospholipase D (metabolism)
• Platelet Activating Factor (physiology)
• Polyunsaturated Alkamides
• Rats
• Rats, Sprague-Dawley