Kirsten sarcoma virus-immortalized mast cell lines. Reversible inhibition of growth by dexamethasone and evidence for the presence of an autocrine growth factor.
Expansion of mast cell numbers occurs in vivo during certain inflammatory reactions, including active fibrosis, parasite infestations, and immediate hypersensitivity reactions. T cell-produced cytokines, including IL-3 and IL-4, are thought to control this mast cell proliferation in part, and glucocorticoid regulation of T cell-produced cytokines is thought to account for diminished mast cell proliferation during administration of glucocorticoids in vivo. Here we show that glucocorticoids have a direct inhibitory effect on proliferation of Kirsten sarcoma virus-immortalized mast cells (KiSV-MC) in vitro, with an ID50 of 1.0 +/- 0.2 nM dexamethasone (mean +/- SD, n = 4). At 10 nM dexamethasone, KiSV-MC proliferation was inhibited by 83 +/- 5% (mean +/- SD, n = 4). As determined by trypan blue staining and [3H]TdR incorporation, the glucocorticoid-mediated growth inhibition was due to diminished mast cell proliferation rather than cell death and was completely reversible after 6 days of glucocorticoid treatment. By cell cycle analysis, glucocorticoids diminished the percentage of mast cells in S phase and increased the percentage in G0-G1 phase. Although we show that the KiSV-MC proliferate via an autocrine mechanism, glucocorticoid treatment of the KiSV-MC did not inhibit their production of the autocrine growth factor. During 6 days of treatment with 1 to 1000 nM dexamethasone, mast cell carboxypeptidase activity increased by a maximum of 3.5-fold. In contrast, total chymotryptic and tryptic esterase activities diminished by as much as 40% with dexamethasone treatment. We conclude that glucocorticoids directly affect mast cell growth and differentiation at levels equal to the reported Kd for glucocorticoid receptors on other immune cells.
Tchekneva
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Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
Serafin
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D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D003907:Dexamethasone / Q000494:pharmacology*; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D007708:Kirsten murine sarcoma virus; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000382:microbiology*; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D006133:Growth Substances; D012333:RNA, Messenger; D015735:Mifepristone; D003907:Dexamethasone; D010450:Endopeptidases