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The Antineoplastic Agent Bryostatin-1 Differentially Regulates IFN- Receptor Subunits in Monocytic Cells: Transcriptional and Posttranscriptional Control of IFN-R2¹

Carmen S. Garcia^2,*, Rafael E. Curiel^2,*, James M. Mwatibo^*, Sidney Pestka, Huifen Li and Igor Espinoza-Delgado^3,

^* Department of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Medical Center, New Orleans, LA 70112; Department of Molecular Genetics and Microbiology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854; and Hematology-Oncology Section, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224

Bryostatin-1 (Bryo-1) is a potent ligand and modulator of protein kinase C that exerts antineoplastic and immunomodulatory activities both in vitro and in vivo. We have previously reported that Bryo-1 synergized with IFN- to induce NO synthase and NO by macrophages. To determine whether this effect was associated with changes in levels of IFN-R, we investigated the effects of Bryo-1 on the expression and regulation of IFN-R chains in monocytic cells. Northern blot analysis revealed that Bryo-1 treatment of the human monocytic cell lines MonoMac6 and THP-1 and human monocytes enhanced the expression of IFN-R2 mRNA but did not affect IFN-R1 mRNA expression. Bryo-1 increased IFN-R2 mRNA in a dose-dependent manner as early as 3 h posttreatment. Bryo-1-induced up-regulation of IFN-R2 mRNA levels is not dependent on de novo protein synthesis as shown by cell treatment with the protein-synthesis inhibitor cycloheximide. Bryo-1 treatment increased the IFN-R2 mRNA half-life by 2 h. EMSA analysis from Bryo-1-treated MonoMac6 cells showed an increased nuclear protein binding to the NF-B motif present in the 5' flanking region of the human IFN-R2 promoter that was markedly decreased by pretreatment with the NF-B inhibitor SN50. These results show for the first time that Bryo-1 up-regulates IFN-R2 expression in monocytic cells. Given the pivotal role that IFN- exerts on monocyte activation and in the initiation and outcome of the immune response, the induction of IFN-R2 by Bryo-1 has significant implications in immunomodulation and could overcome some of the immune defects observed in cancer patients.