Review
Cannabinoid receptors and the regulation of immune response

https://doi.org/10.1016/S0009-3084(00)00195-XGet rights and content

Abstract

Cannabinoid research underwent a tremendous increase during the last 10 years. This progress was made possible by the discovery of cannabinoid receptors and the endogenous ligands for these receptors. Cannabinoid research is developing in two major directions: neurobehavioral properties of cannabinoids and the impact of cannabinoids on the immune system. Recent studies characterized the cannabinoid-induced response as a very complex process because of the involvement of multiple signalling pathways linked to cannabinoid receptors or effects elicited by cannabinoids without receptor participation. The objective of this review is to present this complexity as it applies to immune response. The functional properties of cannabinoid receptors, signalling pathways linked to cannabinoid receptors and the modulation of immune response by cannabinoid receptor ligands are discussed. Special attention is given to ‘endocannabinoids’ as immunomodulatory molecules.

Introduction

Marijuana (Cannabis sativa) is one of the oldest drugs of abuse but its medicinal value has also been known by many cultures throughout human history. Indications for the medicinal use of cannabis can be found in ancient Chinese and Egyptian civilizations. Cannabis preparations were included in British and US pharmacopoeias and were used extensively up to the 1930s for treatment of convulsive disorders and as analgesics. In the 1930s, marijuana started to lose medical attention as new, pure pharmaceutical drugs began to appear such as opiates, aspirin and barbiturates which could be given in standard doses with reliable effects. As marijuana's medicinal use began to wane, its recreational use started to increase in Western countries. Shortly thereafter, abuse of marijuana led to withdrawal of cannabis preparations from pharmacopoeias and laws were passed prohibiting its use. The identification of Δ9-tetrahydrocannabinol (Δ9-THC) as a major psychoactive principle in marijuana and its chemical synthesis by Gaani and Mechoulam, 1964 opened a new era of synthetic cannabinoids as pharmacological agents. Δ9-THC preparations have been used, albeit occasionally, for pain relief, as an anti-emetic and appetite stimulant during cancer chemotherapy, as anti-convulsant and analgesic.

A significant increase of interest in cannabinoids developed shortly after pharmacological identification (Devane et al., 1988) and subsequent cloning (Matsuda et al., 1990) of a central CB1 cannabinoid receptor which is expressed mainly by neuronal cells. Subsequent identification of a peripheral CB2 cannabinoid receptor (Munro et al., 1993), which is expressed predominantly by immune cells, revealed a basis for the known, while modest, immunomodulatory effects of cannabis preparations. Thus, the molecular basis for cannabinoid action on the central nervous and immune systems was established.

The identification of N-arachidonoylethanolamine, referred to as anandamide (Devane et al., 1992), and more recently 2-arachidonoylglycerol (2-AG) (Lee et al., 1995, Mechoulam et al., 1995, Sugiura et al., 1995) as endogenous ligands for cannabinoid receptors raised questions about the role of ‘endocannabinoids’ and cannabinoid receptors in the maintenance of physiological homeostasis and in the development of some neuronal and immune system disorders.

Since cannabinoid research initially was primarily of sociological interest, one of its objectives has been to clarify the mechanism of action of natural cannabinoids and their synthetic derivatives. Information concerning cannabinoid-induced responses tends to characterize cannabinoid-induced signalling as an extremely complex event. This complexity is determined by the linkage of multiple signalling cascades to cannabinoid receptors as well as by the apparent non-receptor-mediated action of high doses of cannabinoids. Also, the physiological consequence of cannabinoid receptor activation may depend on the type of cell, the presence of other concomitant signalling events, and the chemical nature of the agonist. In contrast to studies on Δ9-THC and its synthetic analogs, questions regarding the intrinsic role of ‘endocannabinoids’ and their receptor-inactive congeners in cell signalling have been less explored. Nevertheless, a better understanding of the functioning of the endogenous cannabinoid system may help to clarify its possible role in the development of some pathologies like autoimmune disorders and propagation of HIV infection. It is the objective of this review to present information concerning the complexity of cannabinoid receptor-mediated signalling and the resulting modulation in the functioning of the immune system.

Section snippets

Variability and distribution of cannabinoid receptors

Presently, two main subtypes of cannabinoid receptors have been characterized. The first pharmacological evidence for cannabinoid receptors (CB1 cannabinoid receptor) was reported by the Howlett group (Devane et al., 1988) which characterized the binding of radioactive synthetic cannabinoid CP 55, 940 to rat brain homogenates. Two years later, Matsuda et al., (1990) isolated and cloned a complementary DNA that encodes rat brain cannabinoid receptor. Subsequently, human (Gérard et al., 1991) and

Signalling events following activation of cannabinoid receptors

A significant part of information concerning signalling events triggered by cannabinoid receptor activation was obtained using CHO, Cos and AtT cells transfected with CB1/CB2 receptors. While transfected cells offer a useful tool to explore functional properties of receptors, one should take into account the artificial nature of transfected cells and carefully extrapolate the obtained data when compared with cells naturally expressing these receptors. In fact, the number of receptors expressed

The effect of natural and synthetic cannabinoids on immune response

Cannabis sativa preparations were used for centuries in Asian medicine to reduce the severity of pain, inflammation and asthma (Mechoulam, 1986). However, the recent tremendous increase in recreational use of marijuana revealed a deleterious effect of marijuana smoke on defense mechanisms against bacterial and viral infections (Klein, 1999). Recent investigations prompted by the discovery of cannabinoid receptors and their endogenous ligands significantly improved our knowledge concerning

Endocannabinoids and the immune system

N-acylethanolamines became of interest to immunologists almost 50 years ago when antiinflammatory properties of some fractions from peanut oil, soybean lecithin and egg yolk, whose active principle was later identified as N-palmitoylethanolamine, were discovered (Coburn et al., 1954, Long and Martin, 1956, Kuehl et al., 1957). In the late 1960s antiviral and antibacterial properties of N-palmitoylethanolamine were also reported (Perlı́k et al., 1971a, Perlı́k et al., 1971b, Perlı́k et al., 1973

Conclusion

Cannabinoid research has experienced tremendous progress in the last decade, and credit for this fact should be given to the identification of cannabinoid receptors and their endogenous ligands. A range of potent cannabinoid receptor ligands and their selective antagonists/inverse agonists, as well as CB1/CB2 receptor binding antibodies, is now available to ensure additional breakthroughs in our understanding of the functioning of ‘endocannabinoid’ system. The complexity of signalling pathways

Acknowledgements

The author's work was supported in part by United States Public Health Service grant GM45741, INTAS grant 97-1297 and RFBR grant 98-04-48049 and The Hormel Foundation. I thank Dr Harald Schmid, Patricia Schmid and Dr Doug Bibus of the Hormel Institute, University of Minnesota, for helpful discussion during preparation of the manuscript.

References (159)

  • N.E. Buckley et al.

    Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor

    Eur. J. Pharmacol.

    (2000)
  • G.A. Cabral et al.

    Inhibition of macrophage inducible protein expression by delta-9-tetrahydrocannabinol

    Life Sci.

    (1994)
  • G.A. Cabral et al.

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

    Life Sci.

    (1995)
  • G.A. Cabral et al.

    Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease

    J. Neuroimmunol.

    (1998)
  • B. Calandra et al.

    Dual intracellular signaling pathways mediated by the human cannabinoid CB1 receptor

    Eur. J. Pharmacol.

    (1999)
  • P. Carayon et al.

    Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B-cell differentiation

    Blood

    (1998)
  • R.G. Coffey et al.

    Tetrahydrocannabinol inhibition of macrophage nitric oxide production

    Biochem. Pharmacol.

    (1996)
  • R. Condie et al.

    Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2

    J. Biol. Chem.

    (1996)
  • J.M. Derocq et al.

    Cannabinoids enhance human B-cell growth at low nanomolar concentrations

    FEBS Lett.

    (1995)
  • J.M. Derocq et al.

    The endogenous cannabinoid anandamide is a lipid messenger activating cell growth via a cannabinoid receptor-independent pathway in hematopoietic cell lines

    FEBS Lett.

    (1998)
  • J.M. Derocq et al.

    Genomic and functional changes induced by the activation of the peripheral cannabinoid receptor CB2 in the promyelocytic cells HL-60. Possible Involvement of the CB2 receptor in cell differentiation

    J. Biol. Chem.

    (2000)
  • W. Feng et al.

    Effects of CTx and 8-bromo-cAMP on LPS-induced gene expression of cytokines in murine peritoneal macrophages

    Biochem. Biophys. Res. Commun.

    (2000)
  • M. Glass et al.

    Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain

    Neuroscience

    (1997)
  • G. Griffin et al.

    Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system

    Eur. J. Pharmacol.

    (1999)
  • M. Herkenham et al.

    Neuronal localization of cannabinoid receptors in the basal ganglia of the rat

    Brain Res.

    (1991)
  • A.C. Herring et al.

    Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and κB elements by cannabinol, a minimally CNS-active cannabinoid

    Biochem. Pharmacol.

    (1998)
  • C.J. Hillard et al.

    Effects of CB1 cannabinoid receptor activation on cerebellar granule cell nitric oxide synthase activity

    FEBS Lett.

    (1999)
  • D.B. Houston et al.

    Differential receptor-G-protein coupling evoked by dissimilar cannabinoid receptor agonists

    Cell Signal.

    (1998)
  • N.E. Kaminski

    Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression

    Biochem. Pharmacol.

    (1996)
  • N.E. Kaminski

    Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors

    J. Neuroimmunol.

    (1998)
  • N.E. Kaminski

    Inhibition of the cAMP signaling cascade via cannabinoid receptors: a putative mechanism of immune modulation by cannabinoid compounds

    Toxicol. Lett.

    (1998)
  • N.E. Kaminski et al.

    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.

    (1994)
  • T.W. Klein et al.

    Marijuana, immunity and infection

    J. Neuroimmunol.

    (1998)
  • T.W. Klein et al.

    Cannabinoid receptors and immunity

    Immunol. Today

    (1998)
  • W.S. Koh et al.

    Cyclic AMP is an essential factor in immune responses

    Biochem. Biophys. Res. Commun.

    (1995)
  • W.S. Koh et al.

    Inhibition of protein kinase A and cyclic AMP response element (CRE)-specific transcription factor binding by Δ9-tetrahydrocannabinol (Δ9-THC): a putative mechanism of cannabinoid-induced immune modulation

    Biochem. Pharmacol.

    (1997)
  • T. Kuwae et al.

    Biosynthesis and turnover of anandamide and other N-acylethanolamines in peritoneal macrophages

    FEBS Lett.

    (1999)
  • D.A. Long et al.

    Factor in arachis oil depressing sensitivity to tuberculin in B.C.G.-infected guinea pigs

    Lancet

    (1956)
  • Y.D. Luo et al.

    Effects of cannabinoids and cocaine on the mitogen-induced transformations of lymphocytes of human and mouse origins

    Int. J. Immunopharmacol.

    (1992)
  • R. Mechoulam et al.

    Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors

    Biochem. Pharmacol.

    (1995)
  • V. Abadji et al.

    Involvement of the carboxyl terminus of the third intracellular loop of the cannabinoid CB1 receptor in constitutive activation of Gs

    J. Neurochem.

    (1999)
  • L. Aloe et al.

    A proposed autocoid mechanism controlling mastocyte behavior

    Agents Actions

    (1993)
  • E.V. Berdyshev et al.

    Experimentally relevant levels of N-acylethanolamines including anandamide are present in serum-containing cell culture media

    FASEB J.

    (1999)
  • E.V. Berdyshev et al.

    Stress-induced generation of N-acylethanolamines in mouse epidermal JB6 P+ cells

    Biochem. J.

    (2000)
  • M. Bouaboula et al.

    Cannabinoid-receptor expression in human leukocytes

    Eur. J. Biochem.

    (1993)
  • M. Bouaboula et al.

    Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1

    Biochem. J.

    (1995)
  • M. Bouaboula et al.

    Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression

    Eur. J. Biochem.

    (1996)
  • M. Bouaboula et al.

    Gi protein modulation induced by a selective inverse agonist for the peripheral cannabinoid receptor CB2: implication for intracellular signalization cross-regulation

    Mol. Pharmacol.

    (1999)
  • T.H. Burkey et al.

    Δ-9-Tetrahydrocannabinol is a partial agonist of cannabinoid receptors in mouse brain

    Eur. J. Pharmacol.

    (1997)
  • G.A. Cabral et al.

    Delta 9-tetrahydrocannabinol decreases alpha/beta interferon response to herpes simplex virus type 2 in the B6C3F1 mouse

    Proc. Soc. Exp. Biol. Med.

    (1986)
  • Cited by (236)

    View all citing articles on Scopus
    View full text