Lipopolysaccharide Induces Anandamide Synthesis in Macrophages via CD14/MAPK/Phosphoinositide 3-Kinase/NF-κB Independently of Platelet-activating Factor*

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-κB-, 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.

[1]  R. Razdan,et al.  Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. , 2003, Molecular pharmacology.

[2]  S. Mizuno,et al.  γ-Irradiation-induced DNA damage enhances NO production via NF-κB activation in RAW264.7 cells , 2003 .

[3]  G. Appendino,et al.  Anandamide inhibits nuclear factor-kappaB activation through a cannabinoid receptor-independent pathway. , 2003, Molecular pharmacology.

[4]  Lei Wang,et al.  Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  E. Del Giudice,et al.  Cannabinoids ablate release of TNFα in rat microglial cells stimulated with lypopolysaccharide , 2003, Glia.

[6]  T. Freund,et al.  A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. , 2002, Chemistry and physics of lipids.

[7]  E. Bulger,et al.  The Macrophage Response to Endotoxin Requires Platelet Activating Factor , 2002, Shock.

[8]  H. Hansen,et al.  Substantial species differences in relation to formation and degradation of N-acyl-ethanolamine phospholipids in heart tissue: an enzyme activity study. , 2002, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[9]  G. Ertl,et al.  Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. , 2001, Journal of the American College of Cardiology.

[10]  R. Krebsbach,et al.  Activation of PAF receptors results in enhanced synthesis of 2‐arachidonoylglycerol (2‐AG) in immune cells , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  L. Petrocellis,et al.  Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. , 2001, Archives of biochemistry and biophysics.

[12]  B. Cravatt,et al.  Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  A. Sanyal,et al.  Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis , 2001, Nature Medicine.

[14]  D. Cucinotta,et al.  Oxidative stress causes nuclear factor-kappaB activation in acute hypovolemic hemorrhagic shock. , 2001, Free radical biology & medicine.

[15]  N. Mackman,et al.  LPS induction of gene expression in human monocytes. , 2001, Cellular signalling.

[16]  C. Fowler,et al.  Differences in the pharmacological properties of rat and chicken brain fatty acid amidohydrolase , 2000, British journal of pharmacology.

[17]  A. Makriyannis,et al.  Functional CB1 cannabinoid receptors in human vascular endothelial cells. , 2000, The Biochemical journal.

[18]  T. Bonner,et al.  Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  L. Petrocellis,et al.  Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. , 1999, European journal of biochemistry.

[20]  G. Stark,et al.  Activation of Phosphatidylinositol 3-Kinase in Response to Interleukin-1 Leads to Phosphorylation and Activation of the NF-κB p65/RelA Subunit , 1999, Molecular and Cellular Biology.

[21]  J. Swantek,et al.  Lipopolysaccharide-induced Tumor Necrosis Factor-α Promoter Activity Is Inhibitor of Nuclear Factor-κB Kinase-dependent* , 1999, The Journal of Biological Chemistry.

[22]  S. Gardiner,et al.  The influence of antibodies to TNF‐α and IL‐1β on haemodynamic responses to the cytokines, and to lipopolysaccharide, in conscious rats , 1998 .

[23]  S. Burstein,et al.  Anandamide synthesis is induced by arachidonate mobilizing agonists in cells of the immune system. , 1998, Biochimica et biophysica acta.

[24]  G. Kunos,et al.  Platelet‐ and macrophage‐derived endogenous cannabinoids are involved in endotoxin‐induced hypotension , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  K. Waku,et al.  Detection of an endogenous cannabimimetic molecule, 2-arachidonoylglycerol, and cannabinoid CB1 receptor mRNA in human vascular cells: is 2-arachidonoylglycerol a possible vasomodulator? , 1998, Biochemical and biophysical research communications.

[26]  E. Ellis,et al.  Activation of peripheral CB1 cannabinoid receptors in haemorrhagic shock , 1997, Nature.

[27]  W. Campbell,et al.  Accumulation of N‐Arachidonoylethanolamine (Anandamide) into Cerebellar Granule Cells Occurs via Facilitated Diffusion , 1997, Journal of neurochemistry.

[28]  D. Piomelli,et al.  Occurrence and Biosynthesis of Endogenous Cannabinoid Precursor,N-Arachidonoyl Phosphatidylethanolamine, in Rat Brain , 1997, The Journal of Neuroscience.

[29]  Stephen P. Mayfield,et al.  Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides , 1996, Nature.

[30]  A. Yamashita,et al.  Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. , 1996, European journal of biochemistry.

[31]  V. Di Marzo,et al.  Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. , 1996, The Biochemical journal.

[32]  G. Levi,et al.  Induction of Prostanoid Biosynthesis by Bacterial Lipopolysaccharide and Isoproterenol in Rat Microglial Cultures , 1995, Journal of neurochemistry.

[33]  B. Martin,et al.  Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. , 1995, European journal of pharmacology.

[34]  J. Schwartz,et al.  Formation and inactivation of endogenous cannabinoid anandamide in central neurons , 1994, Nature.

[35]  M. Liscovitch,et al.  Lipid second messengers , 1994, Cell.

[36]  C. Thiemermann,et al.  Platelet-activating factor contributes to the induction of nitric oxide synthase by bacterial lipopolysaccharide. , 1993, Circulation research.

[37]  M. Aepfelbacher,et al.  Tumor necrosis factor induces enhanced responses to platelet‐activating factor and differentiation in human monocytic Mono Mac 6 cells , 1993, European journal of immunology.

[38]  W. Buurman,et al.  Involvement of CD14 in lipopolysaccharide-induced tumor necrosis factor-alpha, IL-6 and IL-8 release by human monocytes and alveolar macrophages. , 1993, Journal of immunology.

[39]  P. Baeuerle,et al.  Nuclear factor kappa B, a mediator of lipopolysaccharide effects. , 1993, Immunobiology.

[40]  D. Gibson,et al.  Isolation and structure of a brain constituent that binds to the cannabinoid receptor. , 1992, Science.

[41]  J. Herbert,et al.  Biochemical and pharmacological activities of SR 27417, a highly potent, long-acting platelet-activating factor receptor antagonist. , 1991, The Journal of pharmacology and experimental therapeutics.

[42]  C. Maliszewski.  CD14 and immune response to lipopolysaccharide. , 1991, Science.

[43]  E. Leonard,et al.  Macrophages cultured in vitro release leukotriene B4 and neutrophil attractant/activation protein (interleukin 8) sequentially in response to stimulation with lipopolysaccharide and zymosan. , 1990, Journal of Clinical Investigation.

[44]  P. Henson,et al.  Lipopolysaccharide stimulates monocyte adherence by effects on both the monocyte and the endothelial cell. , 1989, Journal of immunology.

[45]  F. Valone.  Identification of platelet-activating factor receptors in P388D1 murine macrophages. , 1988, Journal of immunology.

[46]  M. Kutner,et al.  Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis , 1988, Hepatology.

[47]  W. Rutter,et al.  Specific Inhibition of Nuclear RNA Polymerase II by α-Amanitin , 1970, Science.

[48]  R. Martı́n-Ruiz,et al.  Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat. , 2002, Gastroenterology.

[49]  P. Braquet,et al.  Platelet-activating factor and cellular immune responses. , 1987, Immunology today.