Stimulation of peripheral cannabinoid receptor CB2 induces MCP-1 and IL-8 gene expression in human promyelocytic cell line HL60

Using the recently developed methodology of nucleic acid microarrays spotte d with specific cDNAs probes belonging to different gene families, we showe d for the first time that nanomolar concentrations of the cannabinoid ligan d CP-55940 upregulated the expression of two different members of the chemo kine gene family: the alpha-chemokine interleukin-8 (IL-8) and the beta-che mokine monocyte chemotactic protein-1 (MCP-1), in the promyelocytic cell li ne HL60 transfected with peripheral cannabinoid receptors (CB2). These geno mic modulations observed on large-scale cDNA arrays were first confirmed by Northern blot studies. Furthermore, ELISA evaluations in culture supernata nts indicated that the cannabinoid-induced activation of these two chemokin e genes was followed by enhanced expression and secretion of the correspond ing proteins. These upregulations initially observed in transfected HL60 ce lls overexpressing CB2 receptors, also occurred in normal nontransfected HL 60 cells. The enhancement of IL-8 and MCP-1 gene transcription and protein production was shown to be pertussis toxin sensitive attesting that this ph enomenon was a G(i) protein-coupled receptor-mediated process as expected f or cannabinoid receptors. More specifically, the abolition of the cannabino id-induced effect by the specific CB2 antagonist SR 144528 indicated a stri ct peripheral cannabinoid-mediated process. Altogether, our data highlight a possible new function of peripheral cannabinoid receptors in the modulati on of immune and inflammatory responses. (C) 1999 Federation of European Bi ochemical Societies.