Effects of methylprednisolone and 21-aminosteroids on mitogen-induced interleukin-6 and tumor necrosis factor-α production in human peripheral blood mononuclear cells

The compounds U-74389G (16-desmethyl tirilazad) and U-74500A are two of the novel series of nonglucocorticoid 21-aminosteroids (or lazaroids) which mimic the high-dose neuroprotective pharmacology of the glucocorticoid methylprednisolone (MP) in the injured CNS. Despite structural analogies to MP, it has been shown previously for a variety of endpoints that lazaroids are devoid of classical glucocorticoid effects. Our objective here was to measure the immunosuppressive effects of these lazaroids directly. Specifically, we have compared the in vitro effects of MP, U-74389G, and U- 74500A on the mitogen-induced cytokine production in human peripheral blood mononuclear cells, which is known to be very sensitive and perhaps the most clinically relevant parameter reflecting immunomodulation. We show that, in contrast to the glucocorticoid MP, both lazaroids at therapeutically relevant concentrations have no significant inhibitory effects on stimulated interleukin-6 and tumor necrosis factor-α production, neither via residual glucocorticoid receptor-mediated activities nor via direct physicochemical effects on cellular membranes. These results strongly support the view that lazaroids lack glucocorticoid activities, but rather exert their tissue protective effects via mechanisms that are independent of glucocorticoid- receptor binding.