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Start Over Author "Sester, D P" Topic bone marrow cells
2 results on '"Sester, D P"'

1. 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.

Author

Sester DP, Beasley SJ, Sweet MJ, Fowles LF, Cronau SL, Stacey KJ, and Hume DA

Subjects
Animals, Bone Marrow Cells cytology, Bone Marrow Cells enzymology, Cell Division immunology, Cell Membrane immunology, Cell Membrane metabolism, Cell Survival immunology, Down-Regulation genetics, Escherichia coli genetics, Lipopolysaccharides immunology, Macrophages cytology, Macrophages enzymology, Mice, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases metabolism, Molecular Mimicry immunology, Phosphorylation, Receptor, Macrophage Colony-Stimulating Factor physiology, Bone Marrow Cells metabolism, CpG Islands immunology, DNA, Bacterial immunology, Down-Regulation immunology, Growth Inhibitors immunology, Macrophages metabolism, Receptor, Macrophage Colony-Stimulating Factor antagonists & inhibitors, Receptor, Macrophage Colony-Stimulating Factor biosynthesis
Abstract

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.

Published
1999

2. Phosphorothioate backbone modification modulates macrophage activation by CpG DNA

Author

Sester, D. P., Naik, S., Shannon Beasley, Hume, D. A., and Stacey, K. J.

Subjects
Cell Survival, Dose-Response Relationship, Immunologic, Down-Regulation, Bone Marrow Cells, Receptor, Macrophage Colony-Stimulating Factor, Nitric Oxide, Cell Line, Mice, Adjuvants, Immunologic, Animals, Humans, Phosphorylation, Promoter Regions, Genetic, HIV Long Terminal Repeat, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Tumor Necrosis Factor-alpha, Macrophages, hemic and immune systems, DNA, respiratory system, Macrophage Activation, Thionucleotides, Interleukin-12, Organophosphates, Gene Expression Regulation, Oligodeoxyribonucleotides, Nucleic Acid Conformation, CpG Islands, Mitogen-Activated Protein Kinases
Abstract

Macrophages respond to unmethylated CpG motifs present in nonmammalian DNA. Stabilized phosphorothioate-modified oligodeoxynucleotides (PS-ODN) containing CpG motifs form the basis of immunotherapeutic agents. In this study, we show that PS-ODN do not perfectly mimic native DNA in activation of macrophages. CpG-containing PS-ODN were active at 10- to 100-fold lower concentrations than corresponding phosphodiester ODN in maintenance of cell viability in the absence of CSF-1, in induction of NO production, and in activation of the IL-12 promoter. These enhancing effects are attributable to both increased stability and rate of uptake of the PS-ODN. By contrast, PS-ODN were almost inactive in down-modulation of the CSF-1R from primary macrophages and activation of the HIV-1 LTR. Delayed or poor activation of signaling components may contribute to this, as PS-ODN were slower and less effective at inducing phosphorylation of the extracellular signal-related kinases 1 and 2. In addition, at high concentrations, non-CpG PS-ODN specifically inhibited responses to CpG DNA, whereas nonstimulatory phosphodiester ODN had no such effect. Although nonstimulatory PS-ODN caused some inhibition of ODN uptake, this did not adequately explain the levels of inhibition of activity. The results demonstrate that the phosphorothioate backbone has both enhancing and inhibitory effects on macrophage responses to CpG DNA.

Published
2000

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