p38 MAPK associated with stereoselective priming by grepafloxacin on O2- production in neutrophils
| Autor: | Masayuki Niwa, Yutaka Kanamori, Masao Hirota, Koichi Hotta, Masako Kumada, Osamu Kozawa, Sadaki Fujimoto |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
MAPK/ERK pathway
MAP Kinase Kinase 4 Neutrophils p38 mitogen-activated protein kinases Pharmacology Biochemistry p38 Mitogen-Activated Protein Kinases Piperazines chemistry.chemical_compound Superoxides Physiology (medical) medicine Humans Enzyme Inhibitors Phosphorylation Protein kinase A Respiratory Burst Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinase 3 biology Kinase Superoxide Cell Membrane JNK Mitogen-Activated Protein Kinases NADPH Oxidases Stereoisomerism Phosphoproteins Grepafloxacin Respiratory burst N-Formylmethionine Leucyl-Phenylalanine Protein Transport chemistry Mitogen-activated protein kinase biology.protein medicine.drug Fluoroquinolones |
| Zdroj: | Free radical biologymedicine. 36(10) |
| ISSN: | 0891-5849 |
| Popis: | Grepafloxacin is an asymmetric fluoroquinolone derivative which possesses high tissue penetrability as well as strong, broad-spectrum antimicrobial activities. We recently found that grepafloxacin induced a priming effect on neutrophil respiratory burst induced by N-formylmethionylleucylphenylalanine. In this report, we elucidate the precise mechanism of the priming by grepafloxacin. The R(+) enantiomer of grepafloxacin induced a more potent priming effect than did S(−)-grepafloxacin. R(+)-Grepafloxacin also produced a more potent translocation of both p47- and p67-phox proteins to membrane fractions of neutrophils. Grepafloxacin-induced primed superoxide generation was significantly inhibited by pretreatment with PD169316 and SB203580, p38 mitogen-activated protein kinase (MAPK) inhibitors, but not with PD98059, a specific inhibitor of the upstream kinase that activates p44/42 MAPK, or SP600125, an inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (JNK). Grepafloxacin strongly phosphorylated p38 MAP kinase but not p44/42 MAPK or JNK. R(+)-Grepafloxacin showed more potent phosphorylation of p38 MAPK than did S(−)-grepafloxacin, in a time- and concentration-dependent manner. PD169316 significantly inhibited R(+)-grepafloxacin-induced translocation of p47-phox protein to the membrane fraction. Interestingly, grepafloxacin stereospecifically bound to the membrane fractions of neutrophils. These results strongly suggest that grepafloxacin stereospecifically primes neutrophil respiratory burst, and p38 MAPK activation is closely related to the grepafloxacin priming. |
| Databáze: | OpenAIRE |
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