Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9913301 | Immunobiology | 2005 | 11 Pages |
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 micro-arrays, 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.
Keywords
TLR9Receptor activity-modifying protein 2CT DNACSF-1HprtTACETLRBMMRPMERK1/2MAPKMicro-arrayinflammationGene regulationToll-like receptorlipopolysaccharidebone marrow-derived macrophageMonocytes/macrophageshypoxanthine-guanine phosphoribosyl transferasemitogen-activated protein kinaseextracellular signal-regulated kinase 1/2
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Cell Biology
Authors
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,