Effects of cannabinoids on LPS‐stimulated inflammatory mediator release from macrophages: Involvement of eicosanoids

Δ9‐Tetrahydrocannabinol (Δ9‐THC) is the major psychoactive component of marijuana and elicits pharmacological actions via cannabinoid receptors. Anandamide (AEA) and 2‐arachidonoyl‐glycerol (2‐AG) are endogenous ligands for cannabinoid receptors, which because of their structural similarities to arachidonic acid (AA), AEA, and 2‐AG could serve as substrates for lipoxygenases and cyclooxygenases (COXs) that metabolize polyunsaturated fatty acids to potent bioactive molecules. In this study, we have compared the effects of Δ9‐THC, AEA, 2‐AG, and another cannabinoid agonist, indomethacin morpholinylamide (IMMA), on lipopolysaccharide (LPS)‐induced NO, IL‐6, and PGE2 release from J774 macrophages. Δ9‐THC, IMMA, and AEA diminish LPS‐induced NO and IL‐6 production in a concentration‐dependent manner. 2‐AG inhibits the production of IL‐6 but slightly increases iNOS‐dependent NO production. Δ9‐THC and IMMA also inhibit LPS‐induced PGE2 production and COX‐2 induction, while AEA and 2‐AG have no effects. These discrepant results of 2‐AG on iNOS and COX‐2 induction might be due to its bioactive metabolites, AA and PGE2, whose incubation cause the potentiation of both iNOS and COX‐2 induction. On the contrary, the AEA metabolite, PGE2‐ethanolamide, influences neither the LPS‐induced NO nor IL‐6 production. Taken together, direct cannabinoid receptor activation leads to anti‐inflammatory action via inhibition of macrophage function. The endogenous cannabinoid, 2‐AG, also serves as a substrate for COX‐catalyzing PGE2 production, which in turn modulates the action of CB2. J. Cell. Biochem. 81: 715–723, 2001. © 2001 Wiley‐Liss, Inc.

[1]  L. Marnett,et al.  Oxygenation of the Endocannabinoid, 2-Arachidonylglycerol, to Glyceryl Prostaglandins by Cyclooxygenase-2* , 2000, The Journal of Biological Chemistry.

[2]  Li Zhu,et al.  Δ-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway1 , 2000, The Journal of Immunology.

[3]  S. Shyue,et al.  Modulation of inducible nitric oxide synthase induction by prostaglandin E2 in macrophages: distinct susceptibility in murine J774 and RAW 264.7 macrophages. , 1999, Prostaglandins & other lipid mediators.

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

[5]  S. Yamamoto,et al.  Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. , 1999, Biochemical pharmacology.

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

[7]  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.

[8]  J. Falck,et al.  Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. , 1998, Molecular pharmacology.

[9]  T. Bilfinger,et al.  Antagonism of LPS and IFN-gamma induction of iNOS in human saphenous vein endothelium by morphine and anandamide by nitric oxide inhibition of adenylate cyclase. , 1998, Journal of cardiovascular pharmacology.

[10]  P. Casellas,et al.  The endogenous cannabinoid anandamide is a lipid messenger activating cell growth via a cannabinoid receptor‐independent pathway in hematopoietic cell lines , 1998, FEBS letters.

[11]  T. Klein,et al.  Marijuana, immunity and infection , 1998, Journal of Neuroimmunology.

[12]  S. Yamamoto,et al.  Anandamide amidohydrolase reacting with 2‐arachidonoylglycerol, another cannabinoid receptor ligand , 1998, FEBS letters.

[13]  C. Ramesha,et al.  Synthesis of Prostaglandin E2 Ethanolamide from Anandamide by Cyclooxygenase-2* , 1997, The Journal of Biological Chemistry.

[14]  G. Annas.  Reefer madness--the federal response to California's medical-marijuana law. , 1997, The New England journal of medicine.

[15]  V. Lagente,et al.  Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. , 1997, European journal of pharmacology.

[16]  B. Martin,et al.  Cannabis: pharmacology and toxicology in animals and humans. , 1996, Addiction.

[17]  P. Prasit,et al.  NEW CLASS OF POTENT LIGANDS FOR THE HUMAN PERIPHERAL CANNABINOID RECEPTOR , 1996 .

[18]  Y. Yamamoto,et al.  Tetrahydrocannabinol inhibition of macrophage nitric oxide production. , 1996, Biochemical pharmacology.

[19]  Y. Jeon,et al.  Attenuation of inducible nitric oxide synthase gene expression by delta 9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor- kappa B/Rel activation. , 1996, Molecular pharmacology.

[20]  W. A. Hill,et al.  Anandamide hydroxylation by brain lipoxygenase:metabolite structures and potencies at the cannabinoid receptor. , 1995, Biochimica et biophysica acta.

[21]  N. Matsuki,et al.  Lipoxygenase-catalyzed oxygenation of arachidonylethanolamide, a cannabinoid receptor agonist. , 1995, Biochimica et biophysica acta.

[22]  F. Blanco,et al.  Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis , 1994, Journal of Neuroimmunology.

[23]  C. Newton,et al.  Secondary immunity to Legionella pneumophila and Th1 activity are suppressed by delta-9-tetrahydrocannabinol injection , 1994, Infection and immunity.

[24]  C. Newton,et al.  Resistance to Legionella pneumophila suppressed by the marijuana component, tetrahydrocannabinol. , 1994, The Journal of infectious diseases.

[25]  K. Mackie,et al.  Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[26]  P. Heinrich,et al.  Interleukin-6 in autoimmune disease. Role of IL-6 in physiology and pathology of the immune defense. , 1993, The Clinical investigator.

[27]  G. Cabral,et al.  delta-9-Tetrahydrocannabinol inhibits cell contact-dependent cytotoxicity of Bacillus Calmétte-Guérin-activated macrophages. , 1993, International journal of immunopharmacology.

[28]  H. Friedman,et al.  Modulation of Interleukin 2 Activity by Δ9-Tetrahydrocannabinol after Stimulation with Concanavalin A, Phytohemagglutinin, or Anti-CD3 Antibody , 1992, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[29]  J. Smith,et al.  Suppressive effect of tetrahydrocannabinol on specific T cell subpopulations in the thymus. , 1992, Thymus.

[30]  S. Specter,et al.  Marijuana and immunity: tetrahydrocannabinol-mediated inhibition of growth and phagocytic activity of the murine macrophage cell line, P388D1. , 1992, International journal of immunopharmacology.

[31]  M. Herkenham,et al.  Cannabinoid receptor localization in brain. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Grimble.  Nutrition and Cytokine Action , 1990, Nutrition Research Reviews.

[33]  R. Razdan,et al.  Structure-activity relationships of the cannabinoids. , 1986, NIDA research monograph.

[34]  S. Smith,et al.  Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus , 1979, Infection and immunity.

[35]  Li Zhu,et al.  D-9-Tetrahydrocannabinol Inhibits Antitumor Immunity by a CB2 Receptor-Mediated, Cytokine-Dependent Pathway , 2000 .

[36]  M. Glass,et al.  Cannabinoid receptors and their endogenous agonists. , 1998, Annual review of pharmacology and toxicology.

[37]  B. Martin,et al.  Molecular neurobiology of the cannabinoid receptor. , 1996, International review of neurobiology.

[38]  Z. Zheng,et al.  Delta-9-tetrahydrocannabinol suppresses tumor necrosis factor alpha maturation and secretion but not its transcription in mouse macrophages. , 1996, International journal of immunopharmacology.

[39]  A. Howlett,et al.  Pharmacology of cannabinoid receptors. , 1995, Annual review of pharmacology and toxicology.

[40]  C. Newton,et al.  Prevention and reversal of delta-9-tetrahydrocannabinol induced depression of natural killer cell activity by interleukin-2. , 1989, International journal of immunopharmacology.

[41]  C. Newton,et al.  In vitro and in vivo suppressive effects of delta-9-tetrahydrocannabinol on interferon production by murine spleen cells. , 1986, International journal of immunopharmacology.