EFFECTS OF METHYLPREDNISOLONE AND 21-AMINOSTEROIDS ON MITOGEN-INDUCEDINTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION IN HUMAN PERIPHERAL-BLOOD MONONUCLEAR-CELLS

The compounds U-74389G (16-desmethyl tirilazao) and U-74500A are two o f the novel series of nonglucocorticoid 21-aminosteroids (or lazaroids ) which mimic the high-dose neuroprotective pharmacology of the glucoc orticoid methylprednisolone (MP) in the injured CNS. Despite structura l analogies to MP, it has been shown previously for a variety of endpo ints that lazaroids are devoid of classical glucocorticoid effects. Ou r objective here was to measure the immunosuppressive effects of these lazaroids directly. Specifically, we have compared the in vitro effec ts of MP, U-74389G, and U-74500A on the mitogen-induced cytokine produ ction in human peripheral blood mononuclear cells, which is known to b e very sensitive and perhaps the most clinically relevant parameter re flecting immunomodulation. We show that, in contrast to the glucocorti coid MP, both lazaroids at therapeutically relevant concentrations hav e no significant inhibitory effects on stimulated interleukin-6 and tu mor necrosis factor-ct production, neither via residual glucocorticoid receptor-mediated activities nor via direct physicochemical effects o n cellular membranes. These results strongly support the view that laz aroids lack glucocorticoid activities, but rather exert their tissue p rotective effects via mechanisms that are independent of glucocorticoi d- receptor binding.