Phospholipase D-dependent and -independent p38MAPK activation pathways are required for superoxide production and chemotactic induction, respectively, in rat neutrophils stimulated by fMLP.
Mitogen-activated protein kinase (MAPK)-mediated signal transduction pathways convert signals by extracellular stimulation into a variety of cellular functions. However, the roles of MAPKs in neutrophils are not well understood. To elucidate the temporal roles of p38MAPK during rat neutrophil activation stimulated by N-formyl-methionyl-leucyl-phenylalanine (fMLP), we examined the kinetics of this enzyme and the role of p38MAPK related to neutrophil functions (superoxide production and chemotaxis). SB203580, a potent and specific inhibitor of p38MAPK, significantly depressed both superoxide production and chemotaxis. Ethanol and 1-butanol, inhibitors of phospholipase D (PLD), suppressed p38MAPK activation in neutrophils under conditions (1 microM fMLP for 5 min) that stimulated superoxide production; and they significantly depressed superoxide production in rat neutrophils stimulated by fMLP. However, neither inhibitor had any effect on the activation of p38MAPK under the conditions (10 nM fMLP for 60 min) that gave optimal chemotaxis. These results indicate that multiple signaling pathways were involved in stimulating p38MAPK and that p38MAPK played different roles in regulating neutrophil function depending on the conditions for stimulation with fMLP. In addition, the activation of p38MAPK occurred dependent on or independent of PLD activation in neutrophils stimulated with fMLP.
Azuma
Yukio
Y
Department of Dental Pharmacology, Asahi University School of Dentistry, 1851-1 Hozumi, Mizuho-City, Gifu 501-0296, Japan. azuma@dent.asahi-u.ac.jp
Kosaka
Keiichi
K
Kashimata
Masanori
M
D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D013481:Superoxides; D000431:Ethanol; D009240:N-Formylmethionine Leucyl-Phenylalanine; D048051:p38 Mitogen-Activated Protein Kinases; D010739:Phospholipase D; C106801:phospholipase D1