The Journal of cell biology, 2006-03, Vol.172 (7), p.1057-1068
2006
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Details
- Autor(en) / Beteiligte
- Titel
- CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion
- Ist Teil von
- The Journal of cell biology, 2006-03, Vol.172 (7), p.1057-1068
- Ort / Verlag
- United States: The Rockefeller University Press
- Erscheinungsjahr
- 2006
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Toll-like receptors (TLRs) recognize molecular patterns preferentially expressed by pathogens. In endosomes, TLR9 is activated by unmethylated bacterial DNA, resulting in proinflammatory cytokine secretion via the adaptor protein MyD88. We demonstrate that CpG oligonucleotides activate a TLR9-independent pathway initiated by two Src family kinases, Hck and Lyn, which trigger a tyrosine phosphorylation-mediated signaling cascade. This cascade induces actin cytoskeleton reorganization, resulting in cell spreading, adhesion, and motility. CpG-induced actin polymerization originates at the plasma membrane, rather than in endosomes. Chloroquine, an inhibitor of CpG-triggered cytokine secretion, blocked TLR9/MyD88-dependent cytokine secretion as expected but failed to inhibit CpG-induced Src family kinase activation and its dependent cellular responses. Knock down of Src family kinase expression or the use of specific kinase inhibitors blocked MyD88-dependent signaling and cytokine secretion, providing evidence that tyrosine phosphorylation is both CpG induced and an upstream requirement for the engagement of TLR9. The Src family pathway intersects the TLR9-MyD88 pathway by promoting the tyrosine phosphorylation of TLR9 and the recruitment of Syk to this receptor.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9525eISSN: 1540-8140DOI: 10.1083/jcb.200508058Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2063763
- Format
- –
- Schlagworte
- Actin Cytoskeleton - drug effects, Actin Cytoskeleton - metabolism, Actins, Adaptor Proteins, Signal Transducing - genetics, Androstadienes - pharmacology, Animals, Antigens, CD - metabolism, B lymphocytes, Cell adhesion, Cell adhesion & migration, Cell Adhesion - drug effects, Cell Line, Tumor, Cell Membrane - drug effects, Cell Membrane - metabolism, Cellular biology, Cellular immunity, Chloroquine - pharmacology, CpG Islands, Cyclin-dependent kinases, Cytokines, Cytokines - secretion, Cytoskeleton - drug effects, Cytoskeleton - metabolism, Dendritic Cells - drug effects, Dendritic Cells - metabolism, Humans, I-kappa B Proteins - metabolism, Interferon-alpha - metabolism, Interleukin-6 - metabolism, Intracellular Signaling Peptides and Proteins - metabolism, Macrophages, Macrophages - drug effects, Macrophages - metabolism, Mice, Mice, Knockout, Models, Biological, Monocytes, Monocytes - drug effects, Monocytes - metabolism, Myeloid Differentiation Factor 88, NF-KappaB Inhibitor alpha, Oligodeoxyribonucleotides - pharmacology, Phosphorylation, Phosphorylation - drug effects, Protein Kinase Inhibitors - pharmacology, Protein-Tyrosine Kinases - metabolism, Proteins, Proto-Oncogene Proteins c-akt - metabolism, Proto-Oncogene Proteins c-hck - genetics, Proto-Oncogene Proteins c-hck - metabolism, Pyrazoles - pharmacology, Pyrimidines - pharmacology, Quinacrine - pharmacology, Receptors, RNA, Small Interfering - genetics, Secretion, src-Family Kinases - antagonists & inhibitors, src-Family Kinases - genetics, src-Family Kinases - metabolism, Syk Kinase, Toll-Like Receptor 9 - genetics, Toll-Like Receptor 9 - metabolism, Toll-Like Receptor 9 - physiology, Tyrosine - metabolism