Glucocorticoids promote the proliferation and antagonize the retinoic acid-mediated growth suppression of Epstein-Barr virus-immortalized B lymphocytes

Michele Quaia, Paola Zancai, Roberta Cariati, Silvana Rizzo, Mauro Boiocchi, Riccardo Dolcetti

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Abstract

Glucocorticoids are able to release Epstein-Barr virus-immortalized (EBV-immortalized) lymphoblastoid B cell lines (LCLs) from the persistent growth arrest induced in these cells by retinoic acid (RA). Moreover, physiologic concentrations of glucocorticoids efficiently antagonized LCL growth inhibition induced by 13-cis-RA; 9-cis-RA; all-trans-RA; and Ro 40- 6055, an RA α receptor (RARα) selective agonist. RARα expression levels, however, were not affected by glucocorticoids. Glucocorticoids, but not other steroid hormones, directly promote LCL proliferation, a phenomenon that was mainly mediated by down-regulation of the cyclin-dependent kinase (CDK) inhibitor p27(Kip-1). Moreover, glucocorticoids contrasted the up-regulation of p27(Kip-1), which was underlying the RA-induced LCL growth arrest, thereby indicating that glucocorticoids and RA signalings probably converge on p27(Kip-1). Both antagonism of RA-mediated growth inhibition and promotion of LCL proliferation were efficiently reversed by the glucocorticoid receptor (GR) antagonist RU486, indicating that all of these effects were mediated by GR. Of note, RU486 also proved to be effective in vivo and, in mice, was able to significantly inhibit the growth of untreated LCLs as well as LCLs growth- arrested by RA in vitro. These findings provide a rational background to further evaluate the possible role of glucocorticoids in the pathogenesis of EBV-related lymphoproliferations of immunosuppressed patients. Moreover, GR antagonists deserve further consideration for their possible efficacy in the management of these disorders, and the use of schedules, including both RA and a GR antagonist, may allow a more thorough evaluation of the therapeutic potential of RA in this setting. (C) 2000 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)711-718
Number of pages8
JournalBlood
Volume96
Issue number2
Publication statusPublished - Jul 15 2000

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ASJC Scopus subject areas

  • Hematology

Cite this

Quaia, M., Zancai, P., Cariati, R., Rizzo, S., Boiocchi, M., & Dolcetti, R. (2000). Glucocorticoids promote the proliferation and antagonize the retinoic acid-mediated growth suppression of Epstein-Barr virus-immortalized B lymphocytes. Blood, 96(2), 711-718.