Genetic determination of the role of PU.1 in macrophage gene expression

Myungsoo Joo, Minjae Kwon, Anser C. Azim, Ruxana T. Sadikot, Timothy S. Blackwell, John W. Christman

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

PU.1, an Ets family transcription factor, mediates macrophage effector function in inflammation by regulating gene expression. But, the extent and nature of PU.1 function in gene expression has not been genetically determined because ablation of PU.1 gene abolishes macrophage development. Here, we epigenetically suppressed PU.1 by stably expressing PU.1 specific siRNA in macrophages, and determined the effect of PU.1 deficiency on expressions of key inflammatory genes: Toll-like receptor 4 (TLR4), cyclooxygenease-2 (COX-2), and macrophage inflammatory protein-1α (MIP-1α). PU.1-silenced cell lines expressed lower TLR4 mRNA and COX-2 protein, but higher MIP-1α protein, than controls. Over-expression of PU.1 suppressed lipopolysaccharide-induced MIP-1α production. PU.1 occupied proximal and distal cognate sites in the endogenous MIP-1α promoter, but dissociated only from the distal sites in response to lipopolysaccharide, suggesting a novel negative regulatory mechanism by PU.1. Together, our results defined PU.1 function in differentially regulating expressions of TLR4, COX-2, and MIP-1α.

Original languageEnglish (US)
Pages (from-to)97-102
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume372
Issue number1
DOIs
StatePublished - Jul 18 2008
Externally publishedYes

Keywords

  • COX-2
  • Epigenetic suppression
  • Gene regulation
  • Inflammation
  • MIP-1α
  • Macrophages
  • PU.1
  • TLR4

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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