Anandamide inhibits macrophage-mediated killing of tumor necrosis factor-sensitive cells

Cabral, Guy A.; Toney, Denise M.; Fischer-Stenger, Krista; Harrison, Matthew P.; Marciano‐Cabral, Francine

doi:10.1016/0024-3205(95)00190-h

Cited by 65 publications

(34 citation statements)

References 17 publications

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“…␦ 9 -Tetrahydrocannabinol (THC), the major psychoactive component of marijuana, has been shown to inhibit the proliferation and phagocytic activity of murine P388D 1 cells (Tang et al, 1992) and to reduce the amount of TNF-␣ and nitric oxide produced by murine RAW264.7 cells in response to bacterial lipopolysaccharide (LPS) (Fischer-Stenger et al, 1993;Jeon et al, 1996). In addition, THC and anandamide, a putative endogenous cannabinoid receptor ligand, have been reported to inhibit peritoneal macrophage-medi-ated killing of TNF-␣ sensitive murine L929 fibroblasts (Cabral et al, 1995;Devane et al, 1992). Taken together, these studies indicate that endogenous and exogenous cannabinoids have the ability to modulate various macrophage activities.…”

Section: Introductionmentioning

confidence: 89%

Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells

Puffenbarger

Boothe

Cabral

2000

Glia

223

112

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The effect of cannabinoids on the induction of cytokine mRNA by rat microglial cells was examined. Exposure of neonatal rat cortical microglial cells to the exogenous cannabinoid δ9‐tetrahydrocannabinol (THC) resulted in reduced amounts of lipopolysaccharide (LPS)‐induced mRNAs for IL‐1α, IL‐1β, IL‐6, and TNF‐α. Of these cytokine mRNAs, the response of that for IL‐6 was exquisitely sensitive to THC. Similarly, exposure of microglial cells to the putative endogenous cannabinoid anandamide before LPS treatment resulted in a decrease in cytokine mRNA levels, but not to the same extent as that caused by THC; however, when methanandamide, the non‐hydrolyzable analog of anandamide was tested, its ability to inhibit cytokine mRNA expression was comparable to that of THC. Exposure of microglial cells to either of the paired enantiomers CP55,940 or CP56,667 resulted in similar inhibition of LPS‐induced cytokine mRNA expression. A comparable inhibitory outcome was obtained when the paired enantiomers levonantradol and dextronantradol were employed. Neither the CB1‐selective antagonist SR141716A nor the CB2‐selective antagonist SR144528 was able to reverse the inhibition of cytokine mRNA expression by levonantradol. The CB2 antagonist, however, when administered alone augmented the production of cytokine mRNAs. Collectively, these studies demonstrate that cannabinoids can modulate levels of cytokine mRNA in rat microglial cells; however, the inhibition of cytokine mRNA expression is apparently not mediated through either the CB1 or CB2 cannabinoid receptors. GLIA 29:58–69, 2000. © 2000 Wiley‐Liss, Inc.

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Section: Introductionmentioning

confidence: 89%

Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells

Puffenbarger

Boothe

Cabral

2000

Glia

223

112

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“…Although the underlying mechanisms are not fully understood, multiple cannabinoid receptor-dependent as well as receptor-independent processes have been implicated. These include, but are not limited to 1) modulation of excitatory glutamatergic transmissions and synaptic plasticity via presynaptic CB 1 receptors (Molina-Holgado et al, 1997;Marsicano and Lutz, 1999;Gerdeman et al, 2002;reviewed in Alger, 2002;Robbe et al, 2002;Azad et al, 2003;Freund et al, 2003;Piomelli, 2003;Mato et al, 2004), 2) modulation of immune responses and the release of inflammatory mediators by CB 1 , CB 2 , and non CB 1 /CB 2 receptors on neurons, astrocytes, microglia, macrophages, neutrophils and lymphocytes (Watzl et al, 1991;Zheng et al, 1992;FischerStenger et al, 1993;Cabral and Fischer-Stenger, 1994;Kusher et al, 1994;Burnette-Curley and Cabral, 1995;Cabral et al, 1995;reviewed in Friedman et al, 1995;Zheng and Specter, 1996;Shohami et al, 1997;Newton et al, 1998;Srivastava et al, 1998;Gallily et al, 2000;Klein et al, 2000aKlein et al, ,b, 2003Smith et al, 2000;Carlisle et al, 2002;Germain et al, 2002;Killestein et al, 2003;Kaplan et al, 2005;Ramirez et al, 2005;reviewed in Friedman et al, 1995;Stella, 2004;Walter and Stella, 2004;Correa et al, 2005;Croxford and Yamamura, 2005;…”

Section: Central Nervous System Disordersmentioning

confidence: 99%

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

2006

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“…AEA is also generated by macrophages (2), where its bacterial endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock (3,4) and liver cirrhosis (5,6). Macrophage-derived AEA has been also implicated in antiinflammatory effects both in the periphery (7) and in the central nervous system (8,9). AEA is thought to be generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE), through cleavage by a phospholipase D (NAPE-PLD) (10,11), upregulation of which can result in increased tissue levels of AEA (12).…”

mentioning

confidence: 99%

A biosynthetic pathway for anandamide

Liu

Wang²,

Harvey−White³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

409

281

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The endocannabinoid arachidonoyl ethanolamine (anandamide) is a lipid transmitter synthesized and released ''on demand'' by neurons in the brain. Anandamide is also generated by macrophages where its endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock and advanced liver cirrhosis. Anandamide can be generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE) through cleavage by a phospholipase D (NAPE-PLD). Here we document a biosynthetic pathway for anandamide in mouse brain and RAW264.7 macrophages that involves the phospholipase C (PLC)-catalyzed cleavage of NAPE to generate a lipid, phosphoanandamide, which is subsequently dephosphorylated by phosphatases, including PTPN22, previously described as a protein tyrosine phosphatase. Bacterial endotoxin (LPS)-induced synthesis of anandamide in macrophages is mediated exclusively by the PLC͞phosphatase pathway, which is up-regulated by LPS, whereas NAPE-PLD is down-regulated by LPS and functions as a salvage pathway of anandamide synthesis when the PLC͞phosphatase pathway is compromised. Both PTPN22 and endocannabinoids have been implicated in autoimmune diseases, suggesting that the PLC͞phosphatase pathway of anandamide synthesis may be a pharmacotherapeutic target.biosynthesis ͉ phosphatase ͉ phospholipase C ͉ phosphoanandamide T he endocannabinoid N-arachidonoyl ethanolamine (anandamide, AEA) is a lipid transmitter synthesized and released ''on demand'' by neurons in the brain (1). AEA is also generated by macrophages (2), where its bacterial endotoxin (LPS)-induced synthesis has been implicated in the hypotension of septic shock (3, 4) and liver cirrhosis (5, 6). Macrophage-derived AEA has been also implicated in antiinflammatory effects both in the periphery (7) and in the central nervous system (8, 9). AEA is thought to be generated from its membrane precursor, N-arachidonoyl phosphatidylethanolamine (NAPE), through cleavage by a phospholipase D (NAPE-PLD) (10, 11), upregulation of which can result in increased tissue levels of AEA (12). We earlier reported that LPS potently stimulates AEA synthesis in RAW264.7 mouse macrophages, in which it increases both the generation of NAPE from [ 14 C]diarachidonoyl phosphatidylcholine and the conversion of NAPE to AEA (4). Because these effects could be prevented by inhibitors of RNA transcription or protein synthesis (4), we hypothesized that LPS induces the expression of proteins involved in the biosynthesis of AEA, and a subtraction cloning strategy using resting and LPS-treated macrophages may help identifying such proteins. Although a specific N-acyltransferase (NAT) involved in the generation of NAPE has not yet been discovered, a NAPEspecific PLD has been identified and its ability to generate AEA from NAPE has been established (11). The results presented here indicate that, unexpectedly, NAPE-PLD is not involved in the stimulated synthesis of AEA in RAW264.7 macrophages. Instead, we identified the lipid phosphoanandamide (pAEA), which is also presen...

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Anandamide inhibits macrophage-mediated killing of tumor necrosis factor-sensitive cells

Cited by 65 publications

References 17 publications

Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells

Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

A biosynthetic pathway for anandamide

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