Activation of TLR-9 Induces IL-8 Secretion through Peroxynitrite Signaling in Human Neutrophils
| Autor: | Driss El Kebir, Tarek Khreiss, János G. Filep, Levente Jozsef |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
DNA
Bacterial Cell Survival Neutrophils medicine.medical_treatment Immunology In Vitro Techniques Biology Nitric Oxide Neutrophil Activation chemistry.chemical_compound Superoxides Peroxynitrous Acid medicine Animals Humans Immunology and Allergy Secretion RNA Messenger Base Sequence Interleukin-6 Tumor Necrosis Factor-alpha Superoxide Interleukin-8 NF-kappa B DNA Methylation Molecular biology Immunity Innate Cytokine chemistry Toll-Like Receptor 9 Cattle Tumor necrosis factor alpha Nitric Oxide Synthase Signal transduction Proto-Oncogene Proteins c-fos Peroxynitrite Intracellular Signal Transduction |
| Zdroj: | The Journal of Immunology. 176:1195-1202 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.176.2.1195 |
| Popis: | Bacterial DNA containing unmethylated CpG motifs is emerging as an important regulator of functions of human neutrophil granulocytes (polymorphonuclear leukocytes (PMN)). These motifs are recognized by TLR-9. Recent studies indicate that peroxynitrite (ONOO−) may function as an intracellular signal for the production of IL-8, one of the key regulators of leukocyte trafficking in inflammation. In this study we investigated whether bacterial DNA (CpG-DNA) could induce ONOO− signaling in human PMN. Human whole blood, isolated PMN (purity, >95%), and high purity (>99%) PMN respond to CpG-DNA, but not to calf thymus DNA, with secretion of IL-8 and, to a lesser extent, IL-6 and TNF. Methylation of cytosines in CpG-DNA resulted in a complete loss of activity. The endosomal acidification inhibitors, bafilomycin A and chloroquine, inhibited CpG-DNA-induced cytokine release from PMN. CpG-DNA-induced IL-8 mRNA expression and release was also blocked by the NO synthase inhibitor Nω-nitro-l-arginine methyl ester. CpG-DNA evoked concomitant increases in intracellular superoxide and NO levels, leading to enhanced ONOO− formation and, consequently, nuclear accumulation of c-Fos and NF-κB. Pharmacological inhibition of NF-κB activation attenuated ∼75% of CpG-DNA-evoked IL-8 release. These results identify ONOO−-dependent activation of NF-κB and c-Fos as an important mechanism that mediates PMN responses, including IL-8 gene expression and release, to bacterial DNA and unmethylated CpG motifs in particular. Enhanced ONOO− formation represents a mechanism by which bacterial DNA may contribute to prolongation and amplification of the inflammatory response. |
| Databáze: | OpenAIRE |
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