Suppression of CpG‐ODN‐mediated IFN&agr; and TNF&agr; response in human plasmacytoid dendritic cells (pDC) by cannabinoid receptor 2 (CB2)‐specific agonists

Abstract

&NA; Plasmacytoid dendritic cells (pDC) compose 0.2–0.5% of circulating leukocytes but play a significant role in mounting host immune responses. Elevated and chronic activation of pDC are implicated in autoimmune disease like systemic lupus erythematosus and rheumatoid arthritis. &Dgr;9‐tetrahydrocannabinol (THC) is a well characterized cannabinoid with potent anti‐inflammatory activity, but acceptance of THC as a treatment for autoimmune disorders has been hindered due to psychotropic activity. The psychotropic effects of THC are mediated through cannabinoid receptor 1 (CB1) expressed in the central nervous system while the immunomodulatory effects of THC result from THC binding to CB1 and CB2 on immune cells. Synthetic CB2‐selective agonists have been developed to explore immune modulation by cannabinoids in the absence of psychotropic effects. The goal of these studies was to determine if the CB2‐selective agonists, JWH‐015 and JWH‐133, have comparable efficacy to THC in modulating IFN&agr; and TNF&agr; responses by primary human pDC. Treatment with JWH‐133 and JWH‐015 inhibited CpG‐induced IFN&agr; and TNF&agr; responses by pDC. Further, the phosphorylation of IRF7, TBK1, NF&kgr;B, and IKK&ggr;, key events in pDC activation, were suppressed by THC, JWH‐133, and JWH‐015. Likewise, the phosphorylation of AKT at the S473 and T308 residues were differentially modulated by treatment with THC and both JWH compounds. Collectively, these results demonstrate the potential for CB2 targeted therapeutics for treatment of inflammatory conditions involving aberrant pDC activity. HighlightsTHC and the CB2‐selective agonists suppressed the IFN&agr; and TNF&agr; responses by pDC.THC and the CB2‐seletive agonists impaired pIRF7 and pTBK1 induction by CpG in pDC.pNF&kgr;B and pIKK&ggr; induction was decreased by THC and CB2‐selective agonists in pDC.CB2‐selective agonists and THC differentially modulated the phosphorylation of AKT.These results suggest CB2 is a viable target for suppressing pDC activation.