EXPRESSION AND CYTOKINE REGULATION OF GLUCOCORTICOID RECEPTORS IN KAPOSIS-SARCOMA

Development of Kaposi's sarcoma (KS) after glucocorticoid therapy has been observed in a variety of clinical states including human immunode ficiency virus-1 infection and recent in vitro studies provided eviden ce for a direct stimulatory effect of glucocorticoid hormones on KS ce ll proliferation. The importance of glucocorticoids in KS pathogenesis is further highlighted by the finding that glucocorticoids synergize with cytokines to promote acquired immune deficiency syndrome (AIDS)-a ssociated KS (AIDS-KS) growth. Furthermore, cytokine effects were abro gated by the glucocorticoid antagonist RU-486, As glucocorticoid actio n is mediated through activation of their intracellular cognate recept ors, we hypothesized that enhanced responsiveness of AIDS-KS cell to g lucocorticoids may be due to elevated glucocorticoid receptor (GR) con tent, Indeed high expression of GRs in AIDS-KS tumor biopsies was dete cted both at the level of mRNA and protein. Quantitative measurements of GRs in these specimens by a sensitive immunoassay showed that GR co ntent was significantly elevated in the tumor tissue (4663 fmol/mg pro tein) compared with the uninvolved skin of the same patients (2777 fmo l/mg protein), both of which were markedly above the normal skin of he althy donors (893 fmol/mg protein). Immunocytochemical analysis confir med the presence of GRs in the cytoplasm and the nucleus of KS cells. Interestingly, four major KS cytokines, namely interEeukin-1 beta, int erleukin-6, tumor necrosis factor-alpha, and oncostatin M, all of whic h are known autocrine growth factors for AIDS-KS cells, significantly increased the expression of functional. GRs in cultured AIDS-KS cells. The latter result may explain, at least in part, the synergistic effe ct of glucocorticoid and oncostatin M on AIDS-KS cell proliferation. T hus, the high levels of GR expression in AIDS-KS and the up-regulation of GRs by KS-growth-promoting factors may confer enhanced and sustain ed sensitivity to the stimulatory effects of glucocorticoids. The data presented also provide molecular bases for therapeutic interventions targeting GRs in this disease.