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�-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis In Mice Through Cb2 Receptor Activation And Ppar� Pathway (Implications For Ibd)

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Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-β-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the anti-inflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPARγ. Oral treatment with BCP reduced disease activity, colonic macro- and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-α, IL-1β, interferon-γ, and keratinocyte-derived chemokine. BCP treatment also inhibited the activation of extracellular signal-regulated kinase 1/2, nuclear factor κB, IκB-kinase α/β, cAMP response element binding and the expression of caspase-3 and Ki-67. Moreover, BCP enhanced IL-4 levels and forkhead box P3 mRNA expression in the mouse colon and reduced cytokine levels (tumor necrosis factor-α, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2) in a culture of macrophages stimulated with lipopolysaccharide. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effect of BCP. Confirming our results, AM630 reversed the beneficial effect of BCP on pro-inflammatory cytokine expression in IEC-6 cells. These results demonstrate that the anti-inflammatory effect of BCP involves CB2 and the PPARγ pathway and suggest BCP as a possible therapy for the treatment of inflammatorybowel disease.


Inflammatory bowel diseases (IBDs) are a group of chronic diseases that affect the gastrointestinal tract and have been mainly subdivided as ulcerative colitis and Crohn's disease.1 The IBDs are characterized by a strong leukocyte activation and infiltration into the intestinal tissues, the release of proinflammatory cytokines2 and enzymes, and the formation of reactive oxygen species. All of these events can induce an extensive and unbalanced activation of the mucosal immune system, driven by the commensal flora.3

Recent evidence suggests a role for the cannabinoid system in IBD regulation. Cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed in normal human colon4,5 and are up-regulated in IBD colonic tissue. In addition, an enhanced level of endocannabinoids was found in biopsy specimens from patients with ulcerative colitis.5 It is thought that CB1 activation results in a decrease of intestinal hypermotility and hypersecretion, whereas the activation of CB2 results in the inhibition of proinflammatory mediators. In addition, both CB2 and CB1 knockout mice are more susceptible to the development of experimental colitis, and the activation of these receptors is extremely important for the abrogation of intestinal inflammation.6 The role of CB2, however, is directly involved with innate immune system, because CB2 is primarily expressed in immune cells, such as macrophages, CD4+ and CD8+ T cells, monocytes, and polymorphonuclear neutrophils,7,8 which are intimately related to the inflammatory response in IBD.9,10 Although CB2 expression has been recently reported within the central nervous system,11 including the spinal cord, microglial cultures, brainstem, and cortex,12 it has not been associated with the central nervous system side effects of CB1 activation. This observation suggests that CB2 is a more attractive therapeutic target for the treatment of IBDs, such as ulcerative colitis.


Several studies support the notion that endocannabinoids exert their anti-inflammatory properties, at least in part, by the activation of the peroxisome proliferator-activated receptor-gamma (PPARγ) pathway.13,14 PPARγ is a member of the superfamily of nuclear receptors and has important anti-inflammatory activity,15,16 because it inhibits the activation of nuclear factor κB (NFκB) and the

expression of the proinflammatory cytokines IL-1β and tumor necrosis factor-α (TNF-α).17–19 The colon expresses a high density of PPARγ,20,21 and much evidence points to the involvement of the PPARγ receptor in the regulation of intestinal inflammation.20,22


Recently, Gertsch et al23 demonstrated that the sesquiterpene (E)-β-caryophyllene (BCP) selectively binds to CB2 and acts as a full agonist. In confirming this hypothesis, the authors demonstrated that oral administration of this compound exerted potent anti-inflammatory effects in wild-type mice but not in CB2 knockout (Cnr2−/−) mice. However, the mechanisms underlying the anti-inflammatory effects of BCP are not completely understood. BCP could inhibit the pathways triggered by the activation of the Toll-like receptor complex CD14/TLR4/MD2, which typically leads to the expression of proinflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α).24 In addition, BCP suppresses extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2 (JNK1/2) signaling. All of these effects contribute to the anti-inflammatory effects of the sesquiterpene.23 BCP is present in a number of plant species that have been widely used in folk medicine for their anti-inflammatory and healing properties, including wild sage [Cordia curassavica (Jacq.) Roem. & Schult. (synonym: Cordia verbenacea DC.)] and black pepper (Piper nigrum L.).25,26


Because both PPARγ and the cannabinoid system are relevant targets for the treatment of IBD, we investigated the molecular mechanisms underlying the anti-inflammatory effects of oral BCP in experimental colitis induced by dextran sulfate sodium (DSS) administration in mice. The findings suggest that BCP seems to reduce intestinal inflammation through CB2 activation and acts directly or indirectly with the PPARγ nuclear receptor. We therefore suggest BCP as a possible therapy for the treatment of IBD.




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