Cannabinoid receptors and immunity

Klein, Thomas; Newton, Cathy; Friedman, Herman

doi:10.1016/s0167-5699(98)01300-0

Cited by 220 publications

(151 citation statements)

References 58 publications

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“…Cannabinoids, the bioactive components of Cannabis sativa, are immunosuppressors by affecting cell function (Zhu et al, 1998;Mc Coy et al, 1999) and by inhibiting proinflammatory soluble mediators (Klein et al, 2000). On this basis, cannabidiol, the nonpsychoactive cannabinoid, ameliorated chronic inflammation in a mouse model of rheumatoid arthritis (Malfait et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

et al. 2003

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Section: Introductionmentioning

confidence: 99%

Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

et al. 2003

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“…An ester, 2-arachidonoyl glycerol (2-AG) was isolated by us from canine gut (3) and by Sugiura et al from brain (4). Anandamide and 2-AG have been the objects of numerous investigations in various areas of biology and have been found to affect processes in the nervous, cardiovascular, immune, and reproductive systems (5)(6)(7)(8). They interact with many neurotransmitters and affect hormone levels (9)(10).…”

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confidence: 99%

2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB ₁ receptor

Hanŭs

Abu‐Lafi

Fride

et al. 2001

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

694

379

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Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids-arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series-and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB1 cannabinoid receptor (Ki ‫؍‬ 21.2 ؎ 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB2 receptor (Ki > 3 M).W e have reported the isolation and identification of two types of endogenous cannabinoids that bind and activate the known cannabinoid receptors CB 1 and CB 2 . Arachidonoyl ethanolamide (anandamide; ref. 1) and later two more polyunsaturated fatty acid ethanol amides (2) were found in porcine brain. An ester, 2-arachidonoyl glycerol (2-AG) was isolated by us from canine gut (3) and by Sugiura et al. from brain (4). Anandamide and 2-AG have been the objects of numerous investigations in various areas of biology and have been found to affect processes in the nervous, cardiovascular, immune, and reproductive systems (5-8). They interact with many neurotransmitters and affect hormone levels (9-10). This ubiquity of effects led us to look for additional endocannabinoids.We report now that we have isolated from porcine brain a third endocannabinoid, 2-arachidonyl glyceryl ether, which we have named noladin ether ( Fig. 1). Materials and MethodsIsolation of Noladin Ether. Porcine brain (100 g, approximately a single brain) was added to a mixture of chloroform (200 ml) and methanol (200 ml) and mixed in a blender for 2 min. Water (100 ml) was added, and the mixing process was continued for another minute. The mixture was filtered. Two layers were formed. The water-methanol layer was separated and evaporated under reduced pressure. The residue obtained was extracted with methanol. The above isolation was repeated numerous times (from a total of 2.4 kg porcine brain). The extract obtained was chromatographed on a gravity column (i.d. 2.5 cm, height 28 cm, 82 g ICN Silica TSC, 60 A) with hexane͞acetone initially in a ratio of 10:1 (vol͞vol) (400 ml), then 9:1 (100 ml), and finally 4:1 (100 ml). The fractions eluted were monitored for binding to the CB 1 receptor from rat brain synaptosomes (prepared as described below; ref. 11) on the basis of displacement of the potent labeled agonist [ 3 H]HU-243 purchased from Tocris (Bristol, U.K.). The material eluted in fractions 45-54 (10-ml each) was found to bind to the receptor. These fractions were combined and purified further by HPLC (see below). A polar-active compound developed on a TLC plate (silica gel 60 F 254 , Merck) in a hexane͞ acetone (4:1) solvent system gave ...

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“…In contrast, CB2 is restricted to the periphery. CB2 mRNA and protein have been detected in gut epithelia and, interestingly, in many immune cell subsets (8). Low levels of CB2 are documented in T lymphocytes while B lymphocytes, NK cells, and granulocytes display higher receptor densities (6,22).…”

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confidence: 99%

“…The presence of CB2 (and CB1) in immune system cells strongly suggests that endocannabinoids are immunomodulators (7,8,24,25). Indeed, cells of the immune system produce a range of endocannabinoids, but the role of these lipids in immunity is not clear.…”

mentioning

confidence: 99%

Differential Roles of CB1 and CB2 Cannabinoid Receptors in Mast Cells

Samson

Small‐Howard

Shimoda

et al. 2003

The Journal of Immunology

134

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Cannabinoid modulation of immune responses is a pathological consequence of marijuana abuse and a potential outcome of therapeutic application of the drug. Moreover, endogenous cannabinoids are physiological immune regulators. In the present report, we describe alterations in gene transcription that occur after cannabinoid exposure in a mast cell line, RBL2H3. Cannabinoid exposure causes marked changes in the transcript levels for numerous genes, acting both independently of and in concert with immunoreceptor stimulation via FcεRI. In two mast cell lines, we observed mRNA and protein expression corresponding to both CB1 and CB2 cannabinoid receptor isoforms, contrary to the prevailing view that CB1 is restricted to the CNS. We show that coexpression of the two isoforms is not functionally redundant in mast cells. Analysis of signaling pathways downstream of cannabinoid application reveals that activation of extracellular signal-regulated kinase, AKT, and a selected subset of AKT targets is accomplished by CB2 ligands and nonselective CB1/CB2 agonists in mast cells. CB1 inhibition does not affect AKT or extracellular signal-regulated kinase activation by cannabinoids, indicating that CB2 is the predominant regulatory receptor for these kinases in this cell context. CB1 receptors are, however, functional in these mast cells, since they can contribute to suppression of secretory responses.

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Cannabinoid receptors and immunity

Cited by 220 publications

References 58 publications

Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB ₁ receptor

Differential Roles of CB1 and CB2 Cannabinoid Receptors in Mast Cells

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Cannabinoid receptors and immunity

Cited by 220 publications

References 58 publications

Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB 1 receptor

Differential Roles of CB1 and CB2 Cannabinoid Receptors in Mast Cells

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2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB ₁ receptor