ReviewEndocannabinoids and immune regulation☆
Section snippets
Endogenous cannabinoid system
The discovery of cannabinoid receptors occurring naturally throughout the vertebrate body and the availability of highly selective and potent canabimimetics led to the identification of a naturally occurring lipid signaling system termed the endocannabinoid system. Interestingly, the endocannabinoid system dates back very long in the evolution because it exists as an ancient plant signaling system regulating the plant immunity-related genes in response to infection and stress [1]. The
Endocannabinoid receptors in immune system
Endocannabinoids are believed to control immune functions and play a role in immune homeostasis. Immune cells express both CB1 and CB2 receptors, secrete endocannabinoids and have functional cannabinoid transport and breakdown mechanisms [15], [16]. Human peripheral blood immune cells are reported to have different degrees of cannabinoid receptor expression with the following rank order: B cells > NK cells > monocytes > polymorphonuclear neutrophils > CD8 lymphocytes > CD4 lymphocytes [17]. The CB1
Endocannabinoid biosynthesis and signaling in the immune system
There is significant biochemical evidence to suggest that biosynthesis, uptake and degradation of endocannabinoids occur in macrophages and leukocytes [15], [16], [19]. This finding supports the role of endocannabinoids as local modulators of immune and inflammatory reactions. It was observed that both RBL-2H3 basophil cells and J774 macrophages can biosynthesize AEA and PEA through hydrolysis of corresponding N-acylphosphatidylethanolamines. Both these cell lines could inactivate the two
Endocannabinoid system in the CNS immunity and inflammation
The inflammatory network of the CNS is an orchestrated collaboration of neuronal and non-neuronal cells, such as T-lymphocytes, oligodendrocytes, astrocytes and microglial cells. In recent years, there have been several in vitro, in vivo and clinical studies suggesting that endocannabinoid system plays an important role in the cellular network of communication in and between the nervous and immune system during neuronal damage and neuroinflammation. During inflammation in the CNS, there is a
Endocannabinoid and immune modulation
Endocannabinoids have important effects on immune functions. They modulate T- and B-lymphocytes proliferation and apoptosis, macrophage-mediated killing of sensitized cells, inflammatory cytokine production, immune cell activation by inflammatory stimuli, chemotaxis and inflammatory cell migration [44], [45]. The immunosuppressive effect of endocannabinoids on immune cells is primarily considered to be mediated through CB2 receptors by the inhibition of the cAMP/protein kinaseA (PKA) pathway
Lymphocytes and haematopoietic cells
Schwarz et al. [46] demonstrated dose-dependent immunosuppressive effects of AEA on T and B human lymphocyte proliferation. AEA effect on DNA synthesis in T- and B-lymphocytes occurred very rapidly as the exposure of the cells during the final 4 h of culture was sufficient to achieve >40% inhibition. Low doses of AEA caused significant inhibition of lymphocyte proliferation and DNA fragmentation, inducing cell death by apoptosis. 2-AG has been shown to exhibit biological activity in mouse
Macrophages
Macrophages play an important role in both innate and adaptive immunity by mediating their effect through presenting antigen to T cells, phagocytosis of infectious agents and secreting acute phase proteins such as nitric oxide, TNF-α, IL-1 and IL-6. CB1 and CB2 receptors are widely expressed on monocytes/macrophages and microgial cells. AEA has been shown to inhibit macrophage-mediated killing of TNF-sensitive murine L929 fibroblasts [61]. AEA and PEA have also been shown to maximally inhibit
Mast cells
Mast cells are bone marrow derived, multifunctional immune cells populating connective and mucosal tissue as well as nervous system and are involved in inflammatory reactions. Using mast cell lines it was shown that they express both CB1 and CB2 receptors. Both PEA and AEA bound to CB2 receptors but only PEA could down modulate mast cell activation in vitro and this effect was efficiently antagonized by AEA [13]. Endocannabinoids except PEA and PEA derivatives have also been shown to induce a
Dendritic cells (DCs)
DCs play a major role as antigen-presenting cells and in the development of antigen-specific T cell responses. Human dendritic cells have been shown to express both CB1 and CB2 receptors. There have been several reports indicating that the endocannabinoid system plays a critical role in regulating DC growth and maturation [72]. The endogenous cannabinoid system is present in DCs and can be regulated by cell activation [72]. AEA, 2-AG and PEA were observed in lipid extracts from immature
Natural killer cells and neutrophils
Natural killer cells and neutrophils are involved in host defense against cancer and anti-microbial responses. In vitro studies on human NK cells demonstrated that cannabinoids can inhibit the constitutive expression of chemokines, IL-8, MIP1-α, MIP-1β, RANTES, phorbol ester stimulated TNF-α, GM-CSF and IFN-gamma. Studies have demonstrated that cannabinoids can suppress NK cell function such as cytolytic activity in rats, mice and humans, which is a cannabinoid receptor-dependent process [75],
Concluding remarks
The endocannabinoids exhibit complex regulatory effects on the immune system. As summarized in Table 1, endocannabinoids are involved in immune regulation by the suppression of cell activation, inhibition of pro-inflammatory cytokine production, NF-κB-dependent apoptosis and modulation of the functions of T helper subsets: Th1 and Th2. Endocannabnoids (AEA and 2-AG) and their congeners (PEA) can thus be considered as potent immunomodulators. The effect of endocannabinoids depends on cell type,
References (99)
Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection
Chem Phys Lipids
(2000)- et al.
Cannabinoid receptors are coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes
J Biol Chem
(1996) - et al.
Isolation and structure of a brain constituent that binds to the cannabinoid receptor
Science
(1992) - et al.
Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors
Biochem Pharmacol
(1995) - et al.
2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain
Biochem Biophys Res Commun
(1995) Pharmacological actions of cannabinoids
Handb Exp Pharmacol
(2005)- et al.
Modulation of trigeminal sensory neuron activity by the dual cannabinoid-vanilloid agonists anandamide, N-arachidonoyl-dopamine and arachidonyl-2-chloroethylamide
Br J Pharmacol
(2004) - et al.
Formation and inactivation of endogenous cannabinoid anandamide in central neurons
Nature
(1994) - et al.
Functional role of high-affinity anandamide transport, as revealed by selective inhibition
Science
(1997) - et al.
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
Nature
(1996)
The biosynthesis, fate and pharmacological properties of endocannabinoids
Handb Exp Pharmacol
The endogenous cannabinoid system and its role in nociceptive behavior
J Neurobiol
Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide
Proc Natl Acad Sci USA
Oxidative metabolism of endocannabinoids
Prostaglandins Leukot Essent Fatty Acids
Anandamide synthesis is induced by arachidonate mobilizing agonists in cells of the immune system
Biochim Biophys Acta
Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes
J Biol Chem
Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations
Eur J Biochem
Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids
J Pharmacol Exp Ther
Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells
Biochem J
Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes
Arch Biochem Biophys
Human mast cells take up and hydrolyze anandamide under the control of 5-lipoxygenase and do not express cannabinoid receptors
FEBS Lett
Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension
FASEB J
Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and kappaB elements by cannabinol, a minimally CNS-active cannabinoid
Biochem Pharmacol
Activation by 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, of p42/44 mitogen-activated protein kinase in HL-60 cells
J Biochem
The endogenous cannabinoid system protects against colonic inflammation
J Clin Invest
Endocannabinoid system and bowel inflammation
Med Clin (Barc)
Endocannabinoids and liver disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases
Am J Physiol Gastrointest Liver Physiol
Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis
Atherosclerosis
Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development
Free Radic Biol Med
Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism
Mol Pharmacol
The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells
Neuron
Cannabinoids inhibit neurodegeneration in models of multiple sclerosis
Brain
New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis
Br J Pharmacol
Activation of the endocannabinoid system as therapeutic approach in a murine model of multiple sclerosis
FASEB J
Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders
J Leukoc Biol
Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis
J Neuroimmunol
Arvanil inhibits T lymphocyte activation and ameliorates autoimmune encephalomyelitis
J Neuroimmunol
Cannabinoid receptor localization in brain
Proc Natl Acad Sci USA
The endocannabinoid system in targeting inflammatory neurodegenerative diseases
Trends Pharmacol Sci
COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord
BMC Neurol
Pharmacological modulation of the endocannabinoid system in a viral model of multiple sclerosis
J Neurochem
Endocannabinoid-mediated synaptic plasticity in the CNS
Annu Rev Neurosci
The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis
Brain
Cannabinoid-based drugs as anti-inflammatory therapeutics
Nat Rev Immunol
The cannabinoid system and immune modulation
J Leukoc Biol
Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis
J Neuroimmunol
Effects of putative cannabinoid receptor ligands, anandamide and 2-arachidonyl-glycerol, on immune function in B6C3F1 mouse splenocytes
J Pharmacol Exp Ther
Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism
Biochem Pharmacol
Stereospecific effects of (−)- and (+)-7-hydroxy-delta-6-tetrahydrocannabinol-dimethylheptyl on the immune system of mice
Pharmacology
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Supported in part by NIH grants R01AI053703, R01ES09098, R01 AI058300, R01DA016545, R01HL058641 and P01AT003961.