RNA interference of interferon regulatory factor-1 gene expression in THP-1 cell line leads to Toll-like receptor-4 overexpression/activation as well as up-modulation of annexin-II

Neoplasia. 2007 Dec;9(12):1012-20. doi: 10.1593/neo.07640.

Abstract

Interferon regulatory factor-1 (IRF-1) is a candidate transcription factor for the regulation of the Toll-like receptor-4 (TLR-4) gene. Using a small interfering RNA-based (siRNA) process to silence IRF-1 gene expression in the leukemic monocytic cell line THP-1, we investigated whether such a modulation would alter TLR-4 expression and activation status in these cells. The siIRF-1 cells expressed elevated levels of TLR-4 mRNA and protein compared to controls by 90% and 77%, respectively. ICAM.1 protein expression and apoptosis levels were increased by 8.35- and 4.25-fold, respectively. The siIRF-1 cells overexpressed Bax mRNA compared to controls. Proteomic analysis revealed upmodulation of the Annexin-II protein in siIRF-1 THP-1 cells. Myelodysplastic syndrome (MDS) patients with an absence of full-length IRF-1 mRNA also overexpressed Annexin-II. It is plausible that this overexpression may lead to the activation of TLR-4 contributing to the increased apoptosis characterizing MDS.

Keywords: Annexin II; IRF-1; RNAi; TLR-4; myelodysplastic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Annexin A2 / biosynthesis*
  • Annexin A2 / genetics
  • Apoptosis
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Interferon Regulatory Factor-1 / antagonists & inhibitors*
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / physiology
  • Leukemia, Promyelocytic, Acute / metabolism
  • Leukemia, Promyelocytic, Acute / pathology
  • Molecular Sequence Data
  • Monocytes / metabolism*
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / pathology
  • Protein Structure, Tertiary
  • RNA Interference*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Toll-Like Receptor 4 / biosynthesis*
  • Toll-Like Receptor 4 / genetics
  • Transfection
  • bcl-2-Associated X Protein / biosynthesis
  • bcl-2-Associated X Protein / genetics

Substances

  • ANXA2 protein, human
  • Annexin A2
  • BAX protein, human
  • Interferon Regulatory Factor-1
  • RNA, Messenger
  • RNA, Small Interfering
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • bcl-2-Associated X Protein
  • Intercellular Adhesion Molecule-1