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* Department of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, Japan;
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
The Third Department of Internal Medicine, Yokohama City University School of Medicine, Yokohama, Japan
2Correspondence: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1–8 Yamadaoka, Suita, Osaka 565-0871, Japan, E-mail: kwada{at}dent.osaka-u.ac-jp; or C.N.S., Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, 20 Shattuck St., Thorn 724, Boston, MA 02115, USA. E-mail: cnserhan{at}zeus.bwh.harvard.edu
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 LTB4 and LXA4 regulated proliferation and differentiation of murine NSCs that were isolated from embryo brains. Proliferation of NSCs was stimulated by LTB4 (3 to 100 nM) and blocked by receptor antagonist (IC50=2.7 µM). In contrast, LXA4, and its aspirin-triggered-15-epi-LXA4 stable analog attenuated growth of NSCs at as little as 1 nM. Both lipoxygenase (LOX) inhibitors and LTB4 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 LTB4; LXA4 gave the opposite gene expressions. In addition to proliferation, LTB4 induced differentiation of NSCs into neurons as monitored by neurite outgrowth and MAP2 expression. These results indicate for the first time that LTB4 and LXA4 directly regulate proliferation and differentiation of NSCs, suggesting these new pathways may be useful in restoring stem cells.—Wada, K., Arita, M., Nakajima, A., Katayama, K., Kudo, C., Kamisaki, Y., Serhan, C. N. Leukotriene B4 and lipoxin A4 are regulatory signals for neural stem cell proliferation and differentiation.
Key Words: inflammatory mediators • neural inflammation • BLT receptor • ALX receptors • neuron
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