Evidence of an anti-inflammatory effect of mycophenolate mofetil in a murine model of pleurisy.

A promising therapeutic approach to reducing inflammation is to inhibit the production of proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1ß], vascular endothelial growth factor alpha (VEGF-α), and, as shown more recently, interleukin-17 [IL-17]). In the present study, the authors have demonstrated the anti-inflammatory effects of mycophenolate mofetil (MMF) in in vivo experiments and have investigated the mechanism of action underlying those effects. Oral administration of MMF significantly inhibited leukocyte influx during the first (4 hours) and second (48 hours) phases of inflammation in a mouse model of pleurisy caused by carrageenan (P < .01). As expected, MMF suppressed protein levels of TNF-α, IL-1ß, VEGF-α, and IL-17A (P < .01). This inhibitory effect was due to down-regulation of mRNA expression for these proinflammatory cytokines (P < .01). These results provide evidence of MMF-mediated inhibition of proinflammatory cytokines, and these anti-inflammatory effects are assumed to result mainly from the inhibition of the synthesis and release of TNF-α, IL-1ß, VEGF-α, and IL-17A from activated leukocytes. These findings suggest that MMF might be an applicable therapeutic in the regulation of the inflammatory response-a response in which the humoral system plays a pivotal role.

Additional evidence of acute anti-inflammatory effects of cyclosporin A in a murine model of pleurisy.

INTRODUCTION: It is well known that cyclosporin A (CsA) exhibits important anti-inflammatory effects, besides its immunosuppressive activity. However, the mechanisms by which CsA exerts these effects remain unclear. OBJECTIVE: This study evaluated whether the acute administration of CsA significantly interfered in leukocyte migration, exudation, myeloperoxidase (MPO) and adenosine-deaminase activities and nitrate/nitrite levels, in a mouse model of pleurisy. MATERIALS AND METHODS: Pleurisy was induced by carrageenan (1%) treatment and the parameters were analyzed 4 and 48 h after. Groups of animals were previously treated with different doses of CsA and compared with non-treated groups. RESULTS: CsA (0.1-5 mg/kg, intraperitoneal, 1 h before pleurisy induction) inhibited neutrophil migration (P<0.05), but not the exudation that occurred 4 h after pleurisy induction. At this time, CsA (1 mg/kg, 1 h before) also decreased nitrate/nitrite levels and MPO activity (P<0.01). CsA (2 mg/kg, 0.5 h before) was also effective in decreasing mononuclear influx, exudation and nitrate/nitrite levels 48 h after onset of inflammation. CONCLUSIONS: These results indicate that the acute administration of CsA is able to reduce the two leukocyte populations that occur both at 4 and 48 h after pleurisy induction, late exudation (48 h), MPO activity (4 h) and nitrate/nitrite levels (4 and 48 h). Taken together, these findings indicate that CsA has acute anti-inflammatory effects in immunocompetent animals.