Glucocorticoids Induce Kaposi's Sarcoma Cell Proliferation Through the Regulation of Transforming Growth Factor-β

Glucocorticoid (GC) use is known to induce or enhance the growth of Kaposi's sarcoma (KS) in many clinical settings including human immunodeficiency virus infection, collagen vascular disease, lymphoproliferative disorders, and renal transplantation. Because GCs may induce immune suppression and thus tumor growth, we determined whether GCs had a direct effect on KS growth. We found that GCs directly induce the growth of KS cell lines. In examining the mechanism of action of GCs, we did not observe induction of known autocrine growth factors for KS including interleukin-1 (IL-1), IL-6, oncostatin-M, basic fibroblast growth factor (bFGF ), and vascular endothelial growth factor (VEGF ). We thus examined factor(s) that inhibit KS growth. Transforming growth factor-β (TGF-β) is produced by KS cells and has pleiotropic effects, including inhibiting the growth of hematopoietic and endothelial cells. We show that TGF-β is produced by KS cells in both the latent and active forms, and that TGF-β is an autocrine growth inhibitory factor. We then studied the effects of GCs on the regulation of TGF-β and found that GCs do not inhibit TGF-β transcription, but significantly inhibit TGF-β activation. This effect is mediated through regulation of the TGF-β activation pathway. TGF-β is activated by plasmin which is positively regulated by plasminogen activator (PA) and PA receptor (PAR), and negatively regulated by plasminogen activator inhibitor (PAI). GCs downregulated PAR and upregulated PAI. Thus, glucocorticoids enhance KS cell growth through the regulation of TGF-β activation.