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Glucocorticoids induce Kaposi's sarcoma cell proliferation through the
regulation of transforming growth factor-beta
J Cai, T Zheng, M Lotz, Y Zhang, R Masood and P Gill
Department of Internal Medicine, University of Southern California School
of Medicine, Los Angeles, USA.
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-beta (TGF-beta) is produced by KS cells and has pleiotropic effects,
including inhibiting the growth of hematopoietic and endothelial cells. We
show that TGF-beta is produced by KS cells in both the latent and active
forms, and that TGF-beta is an autocrine growth inhibitory factor. We then
studied the effects of GCs on the regulation of TGF-beta and found that GCs
do not inhibit TGF- beta transcription, but significantly inhibit TGF-beta
activation. This effect is mediated through regulation of the TGF-beta
activation pathway. TGF-beta 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-beta activation.
Volume 89,
Issue 5,
pp. 1491-1500,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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