The antineoplastic agent bryostatin-1 differentially regulates IFN-gamma receptor subunits in monocytic cells: transcriptional and posttranscriptional control of IFN-gamma R2

J Immunol. 2006 Aug 15;177(4):2707-16. doi: 10.4049/jimmunol.177.4.2707.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Bryostatins
  • Cell Line
  • Cell Line, Tumor
  • Humans
  • Interferon-gamma / metabolism*
  • Macrolides / pharmacology*
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Protein Subunits / biosynthesis
  • Protein Subunits / genetics
  • RNA Processing, Post-Transcriptional / drug effects*
  • RNA, Messenger / biosynthesis
  • Receptors, Interferon / biosynthesis
  • Receptors, Interferon / genetics*
  • Transcription, Genetic / drug effects*
  • Transcription, Genetic / immunology
  • Up-Regulation / drug effects*
  • Up-Regulation / immunology

Substances

  • Antineoplastic Agents
  • Bryostatins
  • IFNGR2 protein, human
  • Macrolides
  • Protein Subunits
  • RNA, Messenger
  • Receptors, Interferon
  • interferon gamma receptor
  • bryostatin 1
  • Interferon-gamma