LPS regulates a set of genes in primary murine macrophages by antagonising CSF-1 action

David P Sester, Angela Trieu, Kristian Brion, Kate Schroder, Timothy Ravasi, Jodie A Robinson, Rebecca C McDonald, Vera Ripoll, Christine A Wells, Harukazu Suzuki, Yoshihide Hayashizaki, Katryn J Stacey, David A Hume, Matthew J Sweet

Research output: Contribution to journalArticlepeer-review

Abstract

We previously reported that bacterial products such as LPS and CpG DNA down-modulated cell surface levels of the Colony Stimulating Factor (CSF)-1 receptor (CSF-1R) on primary murine macrophages in an all-or-nothing manner. Here we show that the ability of bacterial products to down-modulate the CSF-1R rendered bone marrow-derived macrophages (BMM) unresponsive to CSF-1 as assessed by Akt and ERK1/2 phosphorylation. Using toll-like receptor (tlr)9 as a model CSF-1-repressed gene, we show that LPS induced tlr9 expression in BMM only when CSF-1 was present, suggesting that LPS relieves CSF-1-mediated inhibition to induce gene expression. Using cDNA microarrays, we identified a cluster of similarly CSF-1 repressed genes in BMM. By real time PCR we confirmed that the expression of a selection of these genes, including integral membrane protein 2B (itm2b), receptor activity-modifying protein 2 (ramp2) and macrophage-specific gene 1 (mpg-1), were repressed by CSF-1 and were induced by LPS only in the presence of CSF-1. This pattern of gene regulation was also apparent in thioglycollate-elicited peritoneal macrophages (TEPM). LPS also counteracted CSF-1 action to induce mRNA expression of a number of transcription factors including interferon consensus sequence binding protein 1 (Icsbp1), suggesting that this mechanism leads to transcriptional reprogramming in macrophages. Since the majority of in vitro studies on macrophage biology do not include CSF-1, these genes represent a set of previously uncharacterised LPS-inducible genes. This study identifies a new mechanism of macrophage activation, in which LPS (and other toll-like receptor agonists) regulate gene expression by switching off the CSF-1R signal. This finding also provides a biological relevance to the well-documented ability of macrophage activators to down-modulate surface expression of the CSF-1R.
Original languageEnglish
Pages (from-to)97-107
Number of pages11
JournalImmunobiology
Volume210
Issue number2-4
DOIs
Publication statusPublished - 2005

Keywords

  • Animals
  • DNA-Binding Proteins
  • Gene Expression Regulation
  • Lipopolysaccharides
  • Macrophage Activation
  • Macrophage Colony-Stimulating Factor
  • Macrophages
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger
  • Receptor, Macrophage Colony-Stimulating Factor
  • Receptors, Cell Surface
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 9

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