Glucocorticoids promote the proliferation and antagonize the retinoic acid-mediated growth suppression of Epstein-Barr virus-immortalized B lymphocytes

Glucocorticoids are able to release Epstein-Barr virus-immortalized (EBV-im mortalized) lymphoblastoid B cell lines (LCLs) from the persistent growth a rrest induced in these cells by retinoic acid (RA), Moreover, physiologic c oncentrations of glucocorticoids efficiently antagonized LCL growth inhibit ion induced by 13-cis-RA; 9-cis-RA; all-trans-RA; and Ro 40-6055, an RA alp ha receptor (RAR alpha) selective agonist, RAR alpha expression levels, how ever, were not affected by glucocorticoids, Glucocorticoids, but not other steroid hormones, directly promote LCL proliferation, a phenomenon that was mainly mediated by down-regulation of the cyclin-dependent kinase (CDK) in hibitor p27(Kip-1). Moreover, glucocorticoids contrasted the up-regulation of p27(Kip-1), which was underlying the RA-induced LCL growth arrest, there by indicating that glucocorticoids and RA signalings probably converge on p 27(Kip-1). Both antagonism of RA-mediated growth inhibition and promotion o f LCL proliferation were efficiently reversed by the glucocorticoid recepto r (GR) antagonist RU486, indicating that all of these effects were mediated by GR, Of note, RU486 also proved to be effective in vivo and, in mice, wa s able to significantly inhibit the growth of untreated LCLs as well as LCL s growth-arrested by RA in vitro. These findings provide a rational backgro und to further evaluate the possible role of glucocorticoids in the pathoge nesis of EBV-related lymphoproliferations of immunosuppressed patients. Mor eover, GR antagonists deserve further consideration for their possible effi cacy in the management of these disorders, and the use of schedules, includ ing both RA and a GR antagonist, may allow a more thorough evaluation of th e therapeutic potential of RA in this setting.