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The TLR7/8 agonist CL097 primes N-formyl-methionyl-leucyl-phenylalanine-stimulated NADPH oxidase activation in human neutrophils: critical role of p47phox phosphorylation and the proline isomerase Pin1
- Source :
- Journal of immunology (Baltimore, Md. : 1950). 189(9)
- Publication Year :
- 2012
-
Abstract
- Superoxide anion production by the neutrophil NADPH oxidase plays a key role in host defense; however, excessive superoxide production is believed to participate to inflammatory reactions. Neutrophils express several TLR that recognize a variety of microbial motifs or agonists. The interaction between TLR and their agonists is believed to help neutrophils to recognize and eliminate the pathogen. However, the effects of some TLR agonists on the NADPH oxidase activation and the mechanisms controlling these effects have not been elucidated. In this study, we show that the TLR7/8 agonist CL097 by itself did not induce NADPH oxidase activation in human neutrophils, but induced a dramatic increase of fMLF-stimulated activation. Interestingly, CL097 induced cytochrome b558 translocation to the plasma membrane and the phosphorylation of the NADPH oxidase cytosolic component p47phox on Ser345, Ser328, and Ser315. Phosphorylation of Ser328 and Ser315 was significantly increased in CL097-primed and fMLF-stimulated neutrophils. Phosphorylation of Ser345, Ser328, and Ser315 was decreased by inhibitors of p38 MAPK and the ERK1/2 pathway. Phosphorylation of Ser328 was decreased by a protein kinase C inhibitor. Genistein, a broad-range protein tyrosine kinase inhibitor, inhibited the phosphorylation of these serines. Our results also show that CL097 induced proline isomerase 1 (Pin1) activation and that juglone, a Pin1 inhibitor, inhibited CL097-mediated priming of fMLF-induced p47phox phosphorylation and superoxide production. These results show that the TLR7/8 agonist CL097 induces hyperactivation of the NADPH oxidase by stimulating the phosphorylation of p47phox on selective sites in human neutrophils and suggest that p38 MAPK, ERK1/2, protein kinase C, and Pin1 control this process.
- Subjects :
- Agonist
medicine.drug_class
Neutrophils
p38 mitogen-activated protein kinases
Immunology
chemistry.chemical_compound
medicine
Immunology and Allergy
Humans
Molecular Targeted Therapy
Phosphorylation
Protein kinase A
Inflammation
NADPH oxidase
biology
Kinase
Superoxide
Imidazoles
NADPH Oxidases
Drug Synergism
Peptidylprolyl Isomerase
Molecular biology
Enzyme Activation
N-Formylmethionine Leucyl-Phenylalanine
NIMA-Interacting Peptidylprolyl Isomerase
chemistry
Toll-Like Receptor 7
Toll-Like Receptor 8
PIN1
biology.protein
Quinolines
Reactive Oxygen Species
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 189
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....40109e9e856296b9bc5b20ee812861d2