Bacterial/CpG DNA down-modulates colony stimulating factor-1 receptor surface expression on murine bone marrow-derived macrophages with concomitant growth arrest and factor-independent survival.
Unmethylated CpG motifs within bacterial DNA constitute a pathogen-associated molecular pattern recognized by the innate immune system. Many of the immunomodulatory functions of bacterial DNA can be ascribed to the ability to activate macrophages and dendritic cells. Here we show stimulatory DNA, like LPS, caused growth arrest of murine bone marrow-derived macrophages proliferating in CSF-1. Stimulatory DNA caused selective down-modulation of CSF-1 receptor surface expression. Flow cytometric analysis of CSF-1-deprived bone marrow-derived macrophages revealed that in contrast to the synchronous reduction of CSF-1 receptor upon CSF-1 addition, activating DNA (both bacterial DNA and CpG-containing oligonucleotide) caused rapid removal of receptor from individual cells leading to a bimodal distribution of surface expression at intermediate times or submaximal doses of stimulus. Despite causing growth arrest, both stimulatory DNA and LPS promoted factor-independent survival of bone marrow-derived macrophages, which was associated with phosphorylation of the mitogen-activated protein kinase family members, extracellular-regulated kinase 1 and 2. CSF-1 receptor down-modulation may polarize the professional APC compartment to the more immunostimulatory dendritic cell-like phenotype by suppressing terminal macrophage differentiation mediated by CSF-1.
Sester
D P
DP
Center for Molecular and Cellular Biology, University of Queensland, Australia.
Beasley
S J
SJ
Sweet
M J
MJ
Fowles
L F
LF
Cronau
S L
SL
Stacey
K J
KJ
Hume
D A
DA
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology; D018899:CpG Islands / Q000276:immunology*; D004269:DNA, Bacterial / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004926:Escherichia coli / Q000235:genetics; D006131:Growth Inhibitors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018716:Molecular Mimicry / Q000276:immunology; D010766:Phosphorylation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology
D004269:DNA, Bacterial; D006131:Growth Inhibitors; D008070:Lipopolysaccharides; D016186:Receptor, Macrophage Colony-Stimulating Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases