SIGNALING PATHWAY ASSOCIATED WITH STIMULATION OF CB2 PERIPHERAL CANNABINOID RECEPTOR - INVOLVEMENT OF BOTH MITOGEN-ACTIVATED PROTEIN-KINASEAND INDUCTION OF KROX-24 EXPRESSION

Cannabinoids, known for their psychoactive effects, also possess immun omodulatory properties. The recent isolation and cloning of the G-prot ein-coupled peripheral cannabinoid receptor (CB2), mainly expressed in immune tissues, have provided molecular tools to determine how cannab inoid compounds may mediate immunomodulation. We here investigated the CB2 signaling properties using stably transfected Chinese hamster ova ry cells expressing human CB2. First, we showed that stimulation by a cannabinoid agonist activated mitogen-activated protein (MAP) kinase i n time- and dose-dependent manners. The rank order of potency for MAP kinase activation of cannabinoid agonists correlated well with their b inding capacities. Second, we demonstrated that, following MAP kinase activation, cannabinoids induced the expression of the growth-related gene Krox-24, also known as NGFI-A, zif/268, and egr-1. Pertussis toxi n completely prevented both MAP kinase activation and Krox-24 inductio n, even mon these responses appeared to be dependent of specific prote ine kinase C isoforms and independent of inhibition of adenylyl cyclas e. A similar coupling of CB2 to a mitogenic pathway and to the regulat ion of Krox-24 expression was also observed in human promyelocytic cel ls HL60. Taken together, these findings provide evidence for a functio nal role of the CB2 receptor in gene induction mediated by the MAP kin ase network.