Immunosuppressive properties of rimonabant (SR141716) on human peripheral blood mononuclear cells

Anna Maria Malfitano, Chiara Laezza, Patrizia Gazzerro, Claudia Grimaldi, Maurizio Bifulco. 1University of Salerno, Salerno, Italy, 2Istituto di Endocrinologia e Oncologia Sperimentale (IEOS), Napoli, Italy.

Rimonabant (SR141716) is the first highly selective CB1 cannabinoid receptor antagonist described (Rinaldi-Carmona et al., 1994). Although rimonabant has been shown to be a powerful agent for the treatment of obesity, as assessed by clinical trials (Van Gaal et al., 2005; Pi-Sunyer et al., 2006), its biological mechanism of action is not yet clear. Emerging findings show that SR141716 exerts potential anti-inflammatory action in several experimental animal models (Croci et al., 2003; Costa et al., 2005) and therapeutic potential in obesity-associated inflammatory diseases (Croci & Zarini, 2007). The aim of this study was to investigate potential immunosuppressive properties of rimonabant analysing in vitro effects on human peripheral blood mononuclear cells (PBMCs).

We showed by 3H-thymidine incorporation assay a concentration-dependent inhibitory effect of rimonabant in PBMCs following activation with various mitogen stimuli, CD3-CD28 magnetic beads, OKT3 antibody or phytohemagglutinin (PHA) after 48h of incubation. At the highest concentration used of 10 μM, a significant inhibition of proliferation (p<0.01) was observed (98% with OKT3, 90% with PHA, 84% with CD3CD28). This effect was not accompanied by cell death as we found by flow cytometry following Annexin V staining that 10 μM rimonabant-treated PBMCs did not undergo apoptosis. In order to evaluate potential CB1 receptor antagonist properties of rimonabant we found, using the 3H-thymidine incorporation assay, that at lower and not inhibitory concentrations it does not revert the immunosuppressive properties of the CB1 receptor agonist anandamide, thus suggesting that the CB1 receptor is not involved in rimonabant action. Furthermore, we analysed the effects of rimonabant in the T cell activation pathway, in particular we found by western blot that rimonabant immunomodulation is associated with a decreased nuclear transcription factor NFkB expression. We also found that rimonabant inhibits COX-2 expression in activated PBMCs.

Our results suggest that rimonabant inhibits PBMCs proliferation through a mechanism that involves T cell activation pathway by decreasing NF-kB expression. Furthermore COX-2 inhibition by rimonabant supports a potential role as anti-inflammatory agent. These findings suggest that rimonabant may have therapeutic potential as an immunosuppressive agent in inflammatory disorders.

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