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

doi:10.1016/0006-2952(96)00480-7

Biochemical Pharmacology

Volume 52, Issue 8, 25 October 1996, Pages 1133-1140

https://doi.org/10.1016/0006-2952(96)00480-7 Get rights and content

Abstract

Immune modulation by cannabinoid compounds, although established for several decades, has remained up until recently mechanistically obscure. The identification of a novel class of G-protein coupled receptors that negatively regulate the cyclic adenosine 3′:5′-monophosphate (cAMP) cascade, bind cannabinoids, and are expressed on cells within the immune system has provided new insights into the mechanism for their biologic activity. Although the role of the cAMP cascade in the regulation of immune responses is itself highly controversial, a number of laboratories recently demonstrated that aberrant regulation of this signaling pathway leads to alterations in the expression of critical immunoregulatory genes, cell cycle arrest, and decreased immune function. This profile of effects is strikingly similar to that which is induced in leukocytes in the presence of cannabinoid compounds. In the present commentary, a putative mechanism of immune regulation by cannabinoids is proposed. This mechanism is discussed in the context of decreased cAMP signaling, the transcription factors that are consequently adversely regulated, and immunologically relevant genes that ultimately exhibit altered expression.

References (61)

R Mechoulam et al.
Identification of an endogenous 2-monoglyceride present in canine gut, that binds to cannabinoid receptors
Biochem Pharmacol
(1995)
R Condie et al.
Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and IL-2 expression in the murine T-cell line, EL4.IL-2
J Biol Chem
(1996)
Y-P Hsueh et al.
c-Jun N-terminal kinase but not mitogen-activated protein kinase is sensitive to cAMP inhibition in T lymphocytes
J Biol Chem
(1995)
GM Kammer
The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response
Immunol Today
(1988)
NE 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)
WS Koh et al.
Cyclic AMP is an essential factor in immune responses
Biochem Biophys Res Commun
(1995)
P Watson et al.
Molecular cloning and characterization of the type VII isoform of mammalian adenylyl cyclase expressed widely in mouse tissues and in S49 mouse lymphoma cells
J Biol Chem
(1994)
AR Schatz et al.
Δ⁹-Tetrahydrocannabinol selectively inhibits T-cell dependent humoral immune responses through direct inhibition of accessory T-cell function
Immunopharmacology
(1993)
WS Koh et al.
Expression of functional glucagon receptors on mouse spleenocytes
Life Sci
(1996)
Y Nakano et al.
Contrasting effect of delta-9-tetrahydrocannabinol on IL-2 activity in spleen and lymph node cells of mice of different ages
Life Sci
(1993)

M Koide et al.

Cyclic AMP-elevating agents induce an inducible type of nitric oxide synthase in cultured vascular smooth muscle cells. Synergism with the induction elicited by inflammatory cytokines

J Biol Chem

(1993)

H Friedman et al.

Drugs of abuse and the immune system

DO Freier et al.

Mechanisms of immunotoxicology by drugs of abuse: Cannabinoids and opiates

NE Kaminski

Mechanisms of immune modulation by cannabinoids

WA Devane et al.

Isolation and structure of a brain constituent that binds to the cannabinoid receptor

Science

(1992)

CC Felder et al.

Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction

M Lee et al.

Effects of putative cannabinoid receptor ligands, anandamide and 2-arachidonylglycerol, on immune function in B6C3F1 mouse splenocytes

J Pharmacol Exp Ther

(1995)

LA Matsuda et al.

Structure of a cannabinoid receptor and functional expression of the cloned cDNA

Nature

(1990)

S Munro et al.

Molecular characterization of a peripheral receptor for cannabinoids

Nature

(1993)

M Bouaboula et al.

Cannabinoid-receptor expression in human leukocytes

Eur J Biochem

(1993)

Cited by (42)

Cannabinoid-induced changes in the immune system: The role of microRNAs
2021, International Immunopharmacology
Citation Excerpt :
Since inflammation is necessary in order to initiate the innate and adaptive immune cells, the suppression of inflammation correlates to a weakened viral infection response. This can be shown through the activation of CB2 receptors, preventing the body from effectively fighting viral infections [40–42]. When the CB2 gene was deleted in animals (CB2 negative), it was found that there was an exacerbation in inflammatory effects from an upregulation in immune cell functions [43].
Naturally occurring cannabinoids have been used by humans for their medicinal benefits for over several millennia. While the use of cannabinoids has been strictly regulated in the past century, easing of state regulations has been associated with an increase in use of cannabinoids in the United States. The potential therapeutic applications of cannabinoids have been explored and the anti-inflammatory effect of cannabis-derived cannabinoids has been well-documented. The pharmacological effects of cannabinoids are governed by the modulation of cannabinoid receptors, CB₁ and CB₂, expressed in the central and peripheral tissues. Moreover, growing scientific evidence suggests that the cannabinoid-mediated changes in the immune system involves change in expression of microRNAs (miRNAs). MiRNAs are short non-coding, single-stranded RNA which have the ability to affect post-translational regulation of gene expression. Studies over the past decade have investigated the changes in expression of miRNAs following treatment of various components of the immune system with different chemical modulators of the cannabinoid receptors. Such studies have highlighted the key role played by various miRNAs in driving the observed immunomodulatory effects of cannabinoids. The aim of this review article, therefore, is to summarize the role of miRNAs behind the observed effects of cannabinoids on the overall immune system, rather than focusing on a single disease state.
Cannabinoids Δ<sup>9</sup>-tetrahydrocannabinol and cannabidiol may be effective against methamphetamine induced mitochondrial dysfunction and inflammation by modulation of Toll-like type-4(Toll-like 4) receptors and NF-κB signaling
2019, Medical Hypotheses
Citation Excerpt :
In fact it was suggested that cannabinoids can inhibit cell death by reserve of DNA fragmentation in apoptosis process during neurodegenerative process of METH abuses [72,73]. Endocannabinoid exerts neuroprotection after traumatic brain injury, by inhibition of NF-kB transactivation, can act as pharmacological profile and as novel candidates for treatment of traumatic brain damages [73,74]. Taken together, according to mentioned literatures reports it can be suggested that cannabinoids derivate such as CBD and/or Δ9–THC can be effective against METH-induced mitochondrial dysfunction, neuro-inflammation, and neurodegeneration, in both human and animal subject.
The neurodegeneration, neuro-inflammation and mitochondrial dysfunction which occur by methamphetamine (METH) abuse or administration are serious and motivation therapeutic approaches for inhibition of these types of neurodegeneration. As we know, METH through Toll-like receptors (TLRs), specially type 4, and NF-κB signaling pathway causes neuro-inflammation and mitochondrial dysfunction. Neuroprotective approach for management of METH-induced neurodegeneration, inflammation and mitochondrial dysfunction, through a novel neuroprotective agent is continuously being superior to any kind of other therapeutic strategy. Therefore, the clarification, introduction and development of efficacious novel neuroprotective agent are demanded. During recent years, using new neuroprotective agent with therapeutic probability for treatment of METH-induced neuro-inflammation and mitochondrial dysfunction has been astoundingly increased. Previous studies have stated the neuroprotective and anti-inflammatory roles of cannabinoid derivate such as cannabidiol (CBD) and delta–9–tetrahydrocannabinol (Δ⁹–THC) in multiple neurodegenerative events and diseases. According to literature cannabinoid derivate, by inhibition of TLR4 and activation of NF-κB signaling pathway, exerts their anti-inflammatory and neuroprotective effects and cause mitochondrial biogenesis. Thus we hypothesized that by using cannabinoids in METH dependent subject it would provide neuroprotection against METH-induced neurodegeneration, neuro-inflammation and mitochondrial dysfunction and probably can manage sequels of METH-induced neurochemical abuses via modulation of TLR4/NF-κB signaling pathway. In this article, we tried to discuss our hypothesis regarding the possible role of CBD and Δ⁹–THC, as a potent neuroprotective and anti-inflammatory agents, in inhibition or treatment of METH-induced neurodegeneration, neuro-inflammation and mitochondrial dysfunction through its effects on TLR4/NF-κB signaling pathway.
Cannabis Use and Markers of Systemic Inflammation: The Coronary Artery Risk Development in Young Adults Study
2019, American Journal of Medicine
Citation Excerpt :
Immune cells have been shown to express cannabinoid receptors.20 Upon activation of the cannabinoid receptors, a reduction of T cell proliferation occurs that has been associated with regulation of cytokines such as IL-6.21,22 Pre-clinical studies also indicate that cannabinoid receptors are present on circulating platelets, contributing to platelet function.23
It is unclear whether cannabis use in humans plays a role in the regulation of inflammatory responses. This study aimed to examine cannabis-attributable immunomodulation as manifested in levels of fibrinogen, C-reactive protein (CRP), and interleukin-6 (IL-6).
The Coronary Artery Risk Development in Young Adults (CARDIA) study is a cohort of 5115 African-American and Caucasian males and females enrolled in 1985-1986, and followed up for over 25 years, with repeated measures of cannabis use. Fibrinogen levels were measured at year 5, year 7, and year 20, CRP levels were measured at year 7, year 15, year 20, and year 25, and IL-6 levels were measured at year 20. We estimated the association of cannabis use and each biomarker using generalized estimating equations adjusting for demographic factors, tobacco cigarette smoking, alcohol drinking, and body mass index.
Compared with never use (reference), recent cannabis use was not associated with any of the biomarkers studied here after adjusting for potential confounding variables. Former cannabis use was inversely associated with fibrinogen levels (β = −5.4; 95% confidence interval [CI], −9.9, −0.9), whereas the associations were weaker for serum CRP (β = −0.02; 95% CI, −0.10, 0.06) and IL-6 (β = −0.06; 95% CI, −0.13, 0.02).
A modest inverse association between former cannabis use and fibrinogen was observed. Additional studies are needed to investigate the immunomodulatory effects of cannabis while considering different cannabis preparation and mode of use.
What we know and do not know about the cannabinoid receptor 2 (CB2)
2014, Seminars in Immunology
Citation Excerpt :
The lack of cAMP accumulation attenuates activation of protein kinase A (PKA). Since activated PKA phosphorylates the cAMP response element-binding protein, which is a transcription factor regulating a variety of genes that promote survival, proliferation and differentiation of immune cells; the net result is immune inhibition [104]. The endocannabinoids 2-AG and noladin ether at CB2 were found to inhibit adenylyl cyclase activity, with noladin ether being more potent [25,33,102].
It has been well appreciated that the endocannabinoid system can regulate immune responses via the cannabinoid receptor 2 (CB2), which is primarily expressed by cells of the hematopoietic system. The endocannabinoid system is composed of receptors, ligands and enzymes controlling the synthesis and degradation of endocannabinoids. Along with endocannabinoids, both plant-derived and synthetic cannabinoids have been shown to bind to and signal through CB2 via G proteins leading to both inhibitory and stimulatory signals depending on the biological process. Because no cannabinoid ligand has been identified that only binds to CB2, the generation of mice deficient in CB2 has greatly expanded our knowledge of how CB2 contributes to immune cell development and function in health and disease. In regards to humans, genetic studies have associated CB2 with a variety of human diseases. Here, we review the endocannabinoid system with an emphasis on CB2 and its role in the immune system.
AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: Implications for opioid/cannabinoid interaction studies
2012, Neuropharmacology
Citation Excerpt :
Two cannabinoid receptors have been well characterized: CB1 receptors (CB1Rs), one of the most abundantly expressed G-protein coupled receptors in the central nervous system, and CB2 receptors (CB2Rs) which are localized primarily on immune cells (Howlett et al., 2004). Both CB1Rs and CB2Rs are coupled to the Gi/o-subtype of G-proteins that inhibit the activity of adenylyl cyclase (Kaminski, 1996) and activate mitogen-activated protein (MAP) kinases (Bouaboula et al., 1995, 1996). CB1Rs (Mackie and Hille, 1992) and CB2Rs (Atwood et al., 2012) additionally inhibit the function of voltage gated calcium channels, while only CB1Rs have been shown to modulate the activity of potassium channels (Hampson et al., 1995).
Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). AM-251 and rimonabant are CB1R antagonist/inverse agonists employed to validate opioid–cannabinoid interactions, presumed to act selectively at CB1Rs. Therefore, the potential for direct action of these antagonists at MORs is rarely considered. This study determined if AM-251 and/or rimonabant directly bind and modulate the function of MORs. Surprisingly, AM-251 and rimonabant, but not a third CB1R inverse agonist AM-281, bind with mid-nanomolar affinity to human MORs with a rank order of affinity (K_i) of AM-251 (251 nM) > rimonabant (652 nM) > AM281 (2135 nM). AM-251 and rimonabant, but not AM-281, also competitively antagonize morphine induced G-protein activation in CHO-hMOR cell homogenates (K_b = 719 or 1310 nM, respectively). AM-251 and rimonabant block morphine inhibition of cAMP production, while only AM-251 elicits cAMP rebound in CHO-hMOR cells chronically exposed to morphine. AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent actions of these antagonists may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.
Δ9-Tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells in vitro
2009, Journal of Neuroimmunology
Nanomolar concentrations of Δ9-tetrahydrocannabinol or cannabidiol are demonstrated to enhance mitogen-induced degradation of tryptophan in human peripheral blood mononuclear cells in dependence of CB1- or CB2-receptor activation. In contrast, suppression of this pathway by cannabinoids in the micromolar concentration range was achieved independent of cannabinoid receptor activation. Both cannabinoids also suppressed tryptophan degradation in myelomonocytic THP-1 cells stimulated with lipopolysaccharide. We conclude, that suppression of tryptophan degradation by cannabinoids via indoleamine-2,3-dioxygenase, which is independent of cannabinoid receptor activation, might enhance the availability of tryptophan for serotonin biosynthesis and consequently can be important in the action of cannabinoids to improve mood disturbances.

View all citing articles on Scopus

^☆: This work was supported, in part, by funds from NIDA Grants DA09789 and DA07908.

View full text

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

Abstract

Biochem Pharmacol

J Biol Chem

J Biol Chem

Immunol Today

Biochem Pharmacol

Biochem Biophys Res Commun

J Biol Chem

Immunopharmacology

Life Sci

Life Sci

Cell

Cell

J Biol Chem

J Biol Chem

J Biol Chem

Cell

J Biol Chem

Int Rev Cytol

Cell

Cellular Signal

J Biol Chem

Drugs of abuse and the immune system

Mechanisms of immunotoxicology by drugs of abuse: Cannabinoids and opiates

Mechanisms of immune modulation by cannabinoids

Isolation and structure of a brain constituent that binds to the cannabinoid receptor

Science

Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction

Effects of putative cannabinoid receptor ligands, anandamide and 2-arachidonylglycerol, on immune function in B6C3F1 mouse splenocytes

J Pharmacol Exp Ther

Structure of a cannabinoid receptor and functional expression of the cloned cDNA

Nature

Molecular characterization of a peripheral receptor for cannabinoids

Nature

Cannabinoid-receptor expression in human leukocytes

Eur J Biochem

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