title: Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action?
abstract: The endocannabinoid system is an ancient lipid signaling network which in mammals modulates neuronal functions, inflammatory processes, and is involved in the aetiology of certain human lifestyle diseases, such as Crohn's disease, atherosclerosis and osteoarthritis. The system is able to downregulate stress-related signals that lead to chronic inflammation and certain types of pain, but it is also involved in causing inflammation-associated symptoms, depending on the physiological context. The cannabinoid type-2 (CB(2)) receptor, which unlike the CB(1) receptor does not induce central side effects, has been shown to be a promising therapeutic target. While CB(1) receptor antagonists/inverse agonists are of therapeutic value, also CB(2) receptor ligands including agonists are of pharmacological interest. Although the endocannabinoid system is known to be involved in the regulation of energy homoeostasis and metabolism (mainly via CB(1) receptors) there was hitherto no direct link between food intake and cannabinoid receptor activation. Our recent finding that beta-caryophyllene, a ubiquitous lipohilic plant natural product, selectively binds to the CB(2) receptor and acts as a full agonist is unexpected. Maybe even more unexpected is that oral administration of this dietary compound exerts potent anti-inflammatory effects in wild type mice but not in CB(2) receptor (Cnr2(-/-)) knockout mice. Like other CB(2) ligands also beta-caryophyllene inhibits the pathways triggered by activation of the toll-like receptor complex CD14/TLR4/MD2, which typically lead to the expression of proinflammatory cytokines (IL-1beta, IL-6; IL-8 and TNFalpha) and promotes a TH(1) immune response. In this addendum, the CB(2) receptor-dependent effect of beta-caryophyllene on LPS-triggered activation of the kinases Erk1/2 and JNK1/2 are further discussed with respect to the possibility that both CB(2) inverse agonists and agonists, independent of their G-protein signaling, may block LPS-triggered activation of MAPKs, leading to inhibition of proinflammatory cytokine expression and attenuation of inflammation.
authors.affiliation: Department of Chemistry and Applied Biosciences; Federal Institute of Technology (ETH); Zürich Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
references.citation: Glia. 2000 Jan 1;29(1):58-69
references.pmid: 10594923
references.citation: Cancer Res. 2008 May 15;68(10):3992-8
references.pmid: 18483286
references.citation: J Biol Chem. 2005 Apr 15;280(15):15315-24
references.pmid: 15699045
references.citation: J Biol Chem. 2005 May 6;280(18):18488-97
references.pmid: 15749716
references.citation: Nature. 2005 Apr 7;434(7034):782-6
references.pmid: 15815632
references.citation: FEBS Lett. 2004 Nov 19;577(3):563-9
references.pmid: 15556647
references.citation: Nat Rev Drug Discov. 2008 May;7(5):438-55
references.pmid: 18446159
references.citation: Br J Pharmacol. 2005 Jun;145(4):441-8
references.pmid: 15821753
references.citation: J Biol Chem. 2006 May 19;281(20):14192-206
references.pmid: 16547349
references.citation: J Neuroendocrinol. 2008 May;20 Suppl 1:15-9
references.pmid: 18426494
references.citation: Mol Cell Biol. 1997 Nov;17(11):6274-82
references.pmid: 9343388
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104
references.pmid: 18574142
references.citation: Cell Signal. 2008 Feb;20(2):424-31
references.pmid: 18060741
references.citation: J Pharmacol Exp Ther. 2000 Apr;293(1):136-50
references.pmid: 10734163
references.citation: J Biol Chem. 2008 Apr 25;283(17):11176-88
references.pmid: 18268018
references.citation: Cell Biochem Biophys. 1999;30(3):369-87
references.pmid: 10403057
references.citation: Br J Pharmacol. 2008 Jan;153(2):347-57
references.pmid: 17994109
references.citation: Br J Pharmacol. 2003 Jun;139(4):775-86
references.pmid: 12813001
references.citation: Eur J Pharmacol. 2005 Sep 27;520(1-3):164-71
references.pmid: 16153638
references.citation: Eur J Pharmacol. 2000 Oct 6;406(1):R5-7
references.pmid: 11011050
references.citation: Horm Metab Res. 2007 Aug;39(8):596-600
references.pmid: 17712725
references.citation: Curr Opin Investig Drugs. 2007 May;8(5):373-84
references.pmid: 17520866
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1101-4
references.pmid: 18292184
references.citation: Science. 2007 Jun 8;316(5830):1494-7
references.pmid: 17556587
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14228-33
references.pmid: 10588688
references.citation: Br J Pharmacol. 2008 Jan;153(2):319-34
references.pmid: 17994113
references.citation: FASEB J. 2007 Jun;21(8):1788-800
references.pmid: 17327359
references.citation: J Biol Chem. 2000 Jan 7;275(1):605-12
references.pmid: 10617657
references.citation: Br J Pharmacol. 2008 Jan;153(2):263-70
references.pmid: 17906675
references.citation: J Leukoc Biol. 2007 Dec;82(6):1382-9
references.pmid: 17652447
references.citation: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2210-8
references.pmid: 17660390
references.citation: Mol Neurobiol. 2007 Aug;36(1):68-74
references.pmid: 17952651
references.citation: Br J Pharmacol. 2008 Jan;153(2):226-39
references.pmid: 17906679
references.citation: Rev Physiol Biochem Pharmacol. 2008;160:1-24
references.pmid: 18481028
references.citation: Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1133-4
references.pmid: 18203843
references.citation: Br J Pharmacol. 2008 Jan;153(2):286-9
references.pmid: 17952109
references.citation: J Pharmacol Exp Ther. 2006 Feb;316(2):780-8
references.pmid: 16258021
references.citation: Adv Exp Med Biol. 2007;601:395-413
references.pmid: 17713029
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G78-G87
references.pmid: 18483180