SYNTHETIC GLUCOCORTICOIDS THAT DISSOCIATE TRANSACTIVATION AND AP-1 TRANSREPRESSION EXHIBIT ANTIINFLAMMATORY ACTIVITY IN-VIVO

Some of the most potent antiinflammatory and immunosuppressive agents are synthetic glucocorticoids. However, major side effects severely li mit their therapeutic use. The development of improved glucocorticoid- based drugs will require the separation of beneficial from deleterious effects. One possibility toward this goal is to try to dissociate two main activities of glucocorticoids, i.e. transactivation and transrep ression. Screening of a library of compounds using transactivation and AP-1 transrepression models in transiently transfected cells identifi ed dissociated glucocorticoids, which exert strong AP-1 inhibition but little or no transactivation. Importantly, despite high ligand bindin g affinity, the prototypic dissociated compound, RU24858, acted as a w eak agonist and did not efficiently antagonize dexamethasone-induced t ranscription in transfected cells. Similar results were obtained in he patic HTC cells for the transactivation of the endogenous tyrosine ami no transferase gene (TAT), which encodes one of the enzymes involved i n the glucocorticoid-dependent stimulation of neoglucogenesis. To inve stigate whether dissociated glucocorticoids retained the antiinflammat ory and immunosuppressive potential of classic glucocorticoids, severa l in vitro and in vivo models were used. Indeed, secretion of the proi nflammatory lymphokine interleukin-1 beta was severely inhibited by di ssociated glucocorticoids in human monocytic THP 1 cells. Moreover, in two in vivo models, these compounds exerted an antiinflammatory and i mmunosuppressive activity as potent as that of the classic glucocortic oid prednisolone. These results may lead to an improvement of antiinfl ammatory and immunosuppressive therapies and provide a novel concept f or drug discovery.