A signaling pathway by a new synthetic lipid A analog, ONO-4007, in RAW264.7 cells.
ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. We have reported that ONO-4007 could be a new bio-logical response modifier for the treatment of tumor necrosis factor (TNF)-alpha-sensitive tumors. In this study, we confirmed that ONO-4007 activated a murine macrophage cell line, RAW264.7, and that the activated RAW264.7 cells produced TNF-alpha. RAW264.7 cells stimulated for less than 15 min with ONO-4007 (40 g/ml) did not produce TNF-alpha (less than 4 U/ml). However, 24 h stimulation with ONO-4007 induced TNF-alpha production (more than 256 U/ml) in RAW264.7 cells. Although P38 in mitogen-activated protein kinase of the RAW264.7 cells was not tyrosine phosphorylated by ONO-4007 stimulation, ERK1 of the RAW264.7 cells was tyrosine phosphorylated for 5-15 min by ONO-4007 stimulation. Tyrosine phosphorylation of ERK1 decreased gradually from 15 min after stimulation and almost disappeared 60 min after stimulation. These findings indicate that ONO-4007 stimulates RAW264.7 cells immediately and induces tyrosine phosphorylation of ERK1 in the RAW264.7 cells for 5-15 min. These data suggest that the signal transduction pathway of ONO-4007 may be similar to that of lipopolysaccharide.
Saito
Yukoh
Y
Department of Oral and Maxillofacial Surgery, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan.
Kuramitsu
Yasuhiro
Y
Arai
Hirofumi
H
Kato
Yukari
Y
Fujimoto
Masanori
M
Ita
Masamichi
M
Hayatsu
Yoshikazu
Y
Shinozaki
Fumihiko
F
Nakamura
Kazuyuki
K
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008050:Lipid A; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha