Anti-inflammatory effect of cannabinoid agonist WIN55, 212 on mouse experimental colitis is related to inhibition of p38MAPK

AIM To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid(CB) receptors, WIN55-212-2(WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future. METHODS We established the colitis model in C57BL/6 mice by replacing the animals' water supply with 4% dextran sulfate sodium(DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha(TNF-α) and interleukin-6(IL-6), and the myeloperoxidase(MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase(p38MAPK) and its phosphorylated form(p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580(SB), an inhibitor of p38, was investigated in parallel experiments, andthe data were compared with those from intervention groups of WIN55 and SB alone or used together. RESULTS The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38 MAPK was inhibited. CONCLUSION These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38 MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38 MAPK signaling pathway and the endogenous CB system.

Endogenous cannabinoids may regulate chronic inflammation in aspirin-exacerbated respiratory disease

Aspirin-exacerbated respiratory disease(AERD)is characterized by the triad of chronic rhinosinusitis with nasal polyposis,adult-onset asthma and non-IgE mediated reactions to aspirin and other cyclooxygenase-1(COX-1)inhibitors.Patients with AERD are dependent on COX-1 activity to maintain production of prostaglandin(PG)species,such as PGE2,which maintain physiologic levels of inflammation and limit the production of pro-inflammatory cysteinyl leukotrienes.The endogenous cannabinoid system is a family of immunomodulatory lipids and their innate g-protein coupled receptors that are closely related to arachidonic acid and may modulate inflammation via several pathways,including the direct production of metabolically active prostaglandin glycerol-esters.A recent pilot study has identified the significant up-regulation of the peripherally expressed,type-2 cannabinoid receptor(CB2)in AERD nasal polyps versus control tissues from patients with either allergic fungal rhinosinusitis or no history of chronic sinonasal inflammation.These early findings suggest the involvement of increased endogenous cannabinoid activity in prostaglandin deficient states such as AERD.Future study is needed to explore the significance of these findings,with specific investigation of the impact of CB2 activation on markers of airway inflammation,as well as the potential to measure CB2 expression as a screening biomarker for the evaluation of unrecognized disease.