Possible participation of intracellular platelet-activating factor in NF-kappaB activation in rat peritoneal macrophages.
As we had found previously that thapsigargin, an endomembrane Ca2+-ATPase inhibitor, induces production of intracellular platelet-activating factor (PAF) [Br. J. Pharmacol. 116 (1995) 2141], we decided to investigate the possible roles of intracellular PAF in nuclear factor (NF)-kappaB activation of thapsigargin-stimulated rat peritoneal macrophages. When rat peritoneal macrophages were stimulated with thapsigargin, the level of inhibitory protein of NF-kappaB-alpha (IkappaB-alpha) was decreased and the nuclear translocation of NF-kappaB was increased. The thapsigargin-induced activation of NF-kappaB was inhibited by the PAF synthesis inhibitor SK&F 98625 and the PAF antagonist E6123. Structurally unrelated PAF antagonists such as E5880 and L-652,731 also inhibited the thapsigargin-induced activation of NF-kappaB. Lipopolysaccharide (LPS)-induced activation of NF-kappaB was also suppressed by these drugs. In a culture of rat peritoneal macrophages, exogenously added PAF did not induce degradation of IkappaB-alpha. These findings suggest that the intracellular PAF produced by the stimulation with thapsigargin or LPS is involved in activation of the NF-kappaB pathway.
Tsuyuki
Kousei
K
Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Sendai, Miyagi 980-8578, Japan.
Ichinowatari
Gaku
G
Tanimoto
Atsuo
A
Yamada
Masateru
M
Yaginuma
Hiroshi
H
Ohuchi
Kazuo
K
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D006868:Hydrolysis; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D001381:Azepines; D017931:DNA Primers; D007093:Imidazoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009943:Organophosphorus Compounds; D010880:Piperidines; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; C093303:SK&F 98625; D014230:Triazoles; C072429:E 5880; C068033:E 6123; D019284:Thapsigargin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases