title: A CB2-Selective Cannabinoid Suppresses T-Cell Activities and Increases Tregs and IL-10.
abstract: We have previously shown that agonists selective for the cannabinoid receptor 2 (CB2), including O-1966, inhibit the Mixed Lymphocyte Reaction (MLR), an in vitro correlate of organ graft rejection, predominantly through effects on T-cells. Current studies explored the mechanism of this immunosuppression by O-1966 using mouse spleen cells. Treatment with O-1966 dose-relatedly decreased levels of the active nuclear forms of the transcription factors NF-κB and NFAT in wild-type T-cells, but not T-cells from CB2 knockout (CB2R k/o) mice. Additionally, a gene expression profile of purified T-cells from MLR cultures generated using a PCR T-cell activation array showed that O-1966 decreased mRNA expression of CD40 ligand and CyclinD3, and increased mRNA expression of Src-like-adaptor 2 (SLA2), Suppressor of Cytokine Signaling 5 (SOCS5), and IL-10. The increase in IL-10 was confirmed by measuring IL-10 protein levels in MLR culture supernatants. Further, an increase in the percentage of regulatory T-cells (Tregs) was observed in MLR cultures. Pretreatment with anti-IL-10 resulted in a partial reversal of the inhibition of proliferation and blocked the increase of Tregs. Additionally, O-1966 treatment caused a dose-related decrease in the expression of CD4 in MLR cultures from wild-type, but not CB2R k/o, mice. These data support the potential of CB2-selective agonists as useful therapeutic agents to prolong graft survival in transplant patients, and strengthens their potential as a new class of immunosuppressive agents with broader applicability.
authors.affiliation: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Robinson
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Meissler
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Fan
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.forename: Martin W
authors.initials: MW
authors.lastname: Adler
authors.forename: Toby K
authors.initials: TK
authors.lastname: Eisenstein
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D018920:Coculture Techniques; D003511:Cyclohexanols; D004305:Dose-Response Relationship, Drug; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism*
chemical_list: C531961:1-(4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl)-3-methylcyclohexanol; D000840:Anisoles; D063386:Cannabinoid Receptor Agonists; D003511:Cyclohexanols; C508609:IL10 protein, human; D043885:Receptor, Cannabinoid, CB2; D016753:Interleukin-10