Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation.
Leukotrienes (LTs) and lipoxins (LXs) are lipid mediators that play a key role in regulating acute inflammatory responses. Their roles in neural stem cell (NSC) functions are of interest. We showed here that LTB(4) and LXA(4) regulated proliferation and differentiation of murine NSCs that were isolated from embryo brains. Proliferation of NSCs was stimulated by LTB(4) (3 to 100 nM) and blocked by receptor antagonist (IC(50)=2.7 microM). In contrast, LXA(4), and its aspirin-triggered-15-epi-LXA(4) stable analog attenuated growth of NSCs at as little as 1 nM. Both lipoxygenase (LOX) inhibitors and LTB(4) receptor antagonists caused apoptosis and cell death. Gene chip analysis revealed that growth-related gene expressions such as epidermal growth factor (EGF) receptor, cyclin E, p27, and caspase 8 were tightly regulated by LTB(4); LXA(4) gave the opposite gene expressions. In addition to proliferation, LTB(4) induced differentiation of NSCs into neurons as monitored by neurite outgrowth and MAP2 expression. These results indicate for the first time that LTB(4) and LXA(4) directly regulate proliferation and differentiation of NSCs, suggesting these new pathways may be useful in restoring stem cells.
Wada
Koichiro
K
Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan. kwada@dent.osaka-u.ac-jp
Arita
Makoto
M
Nakajima
Atsushi
A
Katayama
Kazufumi
K
Kudo
Chiho
C
Kamisaki
Yoshinori
Y
Serhan
Charles N
CN
D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000196:embryology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002843:Chromatin / Q000648:ultrastructure; D005260:Female; D007975:Leukotriene B4 / Q000494:pharmacology*; D044045:Lipoxins / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D010666:Phenylpropionates / Q000494:pharmacology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects
D002843:Chromatin; D044045:Lipoxins; D016859:Lipoxygenase Inhibitors; D010666:Phenylpropionates; C040527:lipoxin A4; C067523:ONO-LB 457; D007975:Leukotriene B4