CpG motifs in bacterial DNA delay apoptosis of neutrophil granulocytes
| Autor: | Levente Jozsef, János G. Filep, Tarek Khreiss |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
DNA
Bacterial MAPK/ERK pathway Programmed cell death Cell Survival Neutrophils Apoptosis Receptors Cell Surface Endosomes Protein Serine-Threonine Kinases Biology Biochemistry Membrane Potentials Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Proto-Oncogene Proteins Genetics Animals Humans Phosphorylation Extracellular Signal-Regulated MAP Kinases Molecular Biology Protein kinase B 030304 developmental biology 0303 health sciences Kinase Akt/PKB signaling pathway Cytochromes c Hydrogen-Ion Concentration Molecular biology Mitochondria Rats Toll-Like Receptor 9 Cell biology DNA-Binding Proteins Kinetics CpG site Caspases CpG Islands bcl-Associated Death Protein Carrier Proteins Proto-Oncogene Proteins c-akt 030215 immunology Biotechnology |
| Zdroj: | The FASEB Journal. 18:1776-1778 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.04-2048fje |
| Popis: | Human neutrophil granulocytes die rapidly, and their survival is contingent upon rescue from programmed cell death by signals from the environment. We now show that a novel signal for delaying neutrophil apoptosis is unmethylated CpG motifs prevalent in bacterial DNA (CpG- DNA). Human neutrophils express toll-like receptor 9 that recognizes these motifs. CpG-DNA, but not mammalian DNA or methylated bacterial DNA, markedly enhanced neutrophil viability by delaying spontaneous apoptosis. Endosomal maturation of CpG-DNA is prerequisite for these actions and was coupled to concurrent activation of the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt signaling pathways, leading to phosphorylation of BAD at Ser112 and Ser136, respectively, and to prevention of decreases in mitochondrial transmembrane potential, cytochrome c release and caspase-3 activation. Consistently, pharmacological inhibition of either ERK or phosphatidylinositol 3-kinase partially reversed these actions of CpG-DNA; however, they did not produce additive inhibition. Furthermore, intravenous injection of CpG-DNA (200 microg/kg) into rats evoked slight decreases in blood pressure and induced a modest leukocytosis, whereas it effectively suppressed neutrophil apoptosis as assayed ex vivo. Our results indicate that unmethylated CpG motifs in bacterial DNA promote neutrophil survival by suppressing the apoptotic machinery and may therefore contribute to prolongation and amplification of inflammation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text