Expression and cytokine regulation of glucocorticoid receptors in Kaposi's sarcoma.
Development of Kaposi's sarcoma (KS) after glucocorticoid therapy has been observed in a variety of clinical states including human immunodeficiency virus-1 infection and recent in vitro studies provided evidence for a direct stimulation effect of glucocorticoid hormones on KS cell 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)-associated KS (AIDS-KS) growth. Furthermore, cytokine effects were abrogated by the glucocorticoid antagonist RU-486. As glucocorticoid action is mediated through activation of their intracellular cognate receptors, we hypothesized that enhanced responsiveness of AIDS-KS cells to glucocorticoids may be due to elevated glucocorticoid receptor (GR) content. Indeed, high expression of GRs in AIDS-KS tumor biopsies was detected both at the level of mRNA and protein. Quantitative measurements of GRs in these specimens by a sensitive immunoassay showed that GR content was significantly elevated in the tumor tissue (4663 fmol/mg protein) compared with the uninvolved skin of the same patients (2777 fmol/mg protein), both of which were markedly above the normal skin of healthy donors (893 fmol/mg protein). Immunocytochemical analysis confirmed the presence of GRs in the cytoplasm and the nucleus of KS cells. Interestingly, four major KS cytokines, namely interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and oncostatin M, all of which 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 effect of glucocorticoid and oncostatin M on AIDS-KS cell proliferation. Thus, the high levels of GR expression in AIDS-KS and the up-regulation of GRs by KS-growth-promoting factors may confer enhanced and sustained sensitivity to the stimulatory effects of glucocorticoids. The data presented also provide molecular bases for therapeutic interventions targeting GRs in this disease.
Guo
W X
WX
Department of Pathology, University of Montreal, Canada.
Antakly
T
T
Cadotte
M
M
Kachra
Z
Z
Kunkel
L
L
Masood
R
R
Gill
P
P
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D001483:Base Sequence; D016207:Cytokines / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D012194:RNA-Directed DNA Polymerase; D011863:Radioimmunoassay; D011965:Receptors, Glucocorticoid / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D016207:Cytokines; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D012194:RNA-Directed DNA Polymerase