The antineoplastic agent bryostatin-1 differentially regulates IFN-gamma receptor subunits in monocytic cells: transcriptional and posttranscriptional control of IFN-gamma R2.
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-gamma to induce NO synthase and NO by macrophages. To determine whether this effect was associated with changes in levels of IFN-gammaR, we investigated the effects of Bryo-1 on the expression and regulation of IFN-gammaR 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-gammaR2 mRNA but did not affect IFN-gammaR1 mRNA expression. Bryo-1 increased IFN-gammaR2 mRNA in a dose-dependent manner as early as 3 h posttreatment. Bryo-1-induced up-regulation of IFN-gammaR2 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-gammaR2 mRNA half-life by 2 h. EMSA analysis from Bryo-1-treated MonoMac6 cells showed an increased nuclear protein binding to the NF-kappaB motif present in the 5' flanking region of the human IFN-gammaR2 promoter that was markedly decreased by pretreatment with the NF-kappaB inhibitor SN50. These results show for the first time that Bryo-1 up-regulates IFN-gammaR2 expression in monocytic cells. Given the pivotal role that IFN-gamma exerts on monocyte activation and in the initiation and outcome of the immune response, the induction of IFN-gammaR2 by Bryo-1 has significant implications in immunomodulation and could overcome some of the immune defects observed in cancer patients.
Garcia
Carmen S
CS
Department of Medicine and Stanley S. Scott Cancer Center, Louisiana State University Medical Center, New Orleans, LA 70112, USA.
Curiel
Rafael E
RE
Mwatibo
James M
JM
Pestka
Sidney
S
Li
Huifen
H
Espinoza-Delgado
Igor
I
D000970:Antineoplastic Agents / Q000494:pharmacology*; D054713:Bryostatins; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology; D000096743:Interferon gamma Receptor
D000970:Antineoplastic Agents; D054713:Bryostatins; D007371:Interferon-gamma; D018942:Macrolides; D021122:Protein Subunits; D012333:RNA, Messenger; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C086185:IFNGR2 protein, human; C046785:bryostatin 1