Anti-inflammatory property of the cannabinoid receptor-2-selective agonist JWH-133 in a rodent model of autoimmune uveoretinitis.
Previous studies have shown that cannabinoids have anti-inflammatory and immune-modulating effects, but the precise mechanisms of action remain to be elucidated. In this study, we investigated the effect of JWH 133, a selective agonist for cannabinoid receptor 2, the main receptor expressed on immune cells, in a model of autoimmune disease, experimental autoimmune uveoretinitis (EAU). JWH 133 suppressed EAU in a dose-dependent manner (0.015-15 mg/kg), and the suppressive effect could be achieved in the disease-induction stage and the effector stage. Leukocytes from mice, which had been treated with JWH 133, had diminished responses to retinal peptide and mitogen Con A stimulation in vitro. In vivo JWH 133 treatment also abrogated leukocyte cytokine/chemokine production. Further in vitro studies indicated that JWH 133 down-regulated the TLR4 via Myd88 signal transduction, which may be responsible for its moderate, suppressive effect on antigen presentation. In vivo JWH 133 treatment (1 mg/kg) also suppressed leukocyte trafficking (rolling and infiltration) in inflamed retina as a result of an effect on reducing adhesion molecules CD162 (P-selectin glycoprotein ligand 1) and CD11a (LFA-1) expression on T cells. In conclusion, the cannabinoid agonist JWH 133 has a high in vivo, anti-inflammatory property and may exert its effect via inhibiting the activation and function of autoreactive T cells and preventing leukocyte trafficking into the inflamed tissue.
Xu
Heping
H
Department of Ophthalmology, School of Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. h.xu@abdn.ac.uk
Cheng
Ching L
CL
Chen
Mei
M
Manivannan
Ayyakkannu
A
Cabay
Laurence
L
Pertwee
Roger G
RG
Coutts
Angela
A
Forrester
John V
JV
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000938:Antigen-Presenting Cells / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002186:Cannabinoids / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D020721:Nervous System Autoimmune Disease, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology
D000893:Anti-Inflammatory Agents; D002186:Cannabinoids; D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D043885:Receptor, Cannabinoid, CB2; D051197:Toll-Like Receptor 4; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC