Propentofylline and Iloprost Suppress the Production of TNF-αby Macrophages but Fail to Ameliorate Experimental Autoimmune Encephalomyelitis in Lewis Rats

Abstract

Intracellular cAMP levels can be elevated by activation of cAMP-generating adenylate cyclase (AC) or inhibition of cAMP-cleavage by phosphodiesterases. Elevation of intracellular cAMP levels in immune cells inhibits production of some Th1-cytokines, particularly TNF-α, and results mainly in downregu-lation of the immune response. Experimental autoimmune encephalomyelitis (EAE) of Lewis rats is a disease mediated by type 1 T helper lymphocytes and macrophages and serves as a model of multiple sclerosis. In EAE we therefore tested the immunomodulatory potency of an AC-activating, stable prosta-cyclin analogue, iloprost, and of a potent and non-selective inhibitor of phosphodiesterases, propentofylline, which also has neuroprotective properties.Preventive treatment of Lewis rats with propentofylline (2×10 or 12.5mg/kg/d), iloprost (2×10 or 12.5μg/kg/d), or both did not significantly ameliorate clinical or histological signs of EAE actively induced by immunization with myelin basic protein (MBP) in complete Freund's adjuvant. Furthermore, adoptive transfer EAE (AT-EAE), passively induced by injection of encephalitogenic MBP-specific Th1 lymphocytes, was not altered in its course by the combined application of iloprost (2×10μg/kg/d) and propentofylline (2×20mg/kg/d) starting on the day of cell transfer. In vitro assays demonstrated that iloprost strongly and propentofylline moderately inhibited the production of TNF-α by macrophages and that iloprost in vivo similarly suppressed TNF-α secretion, although this effect was limited to a few hours after a single injection. In contrast to macrophages, TNF-α production by antigen-activated encephalitogenic T helper line cells in vitro was completely resistant to modulation by these agents. In addition, the presence of iloprost, propentofylline, or both drugs during activation of the line cells in vitro did not impair their encephalitogenicity in vivo.The findings delineate immunomodulatory effects of both substances, particularly of iloprost, but fail to support a possible therapeutic role of these agents in autoimmune inflammation of the central nervous system.