Monokine induced by interferon-gamma acts as a neurotrophic factor on PC12 cells and rat primary sympathetic neurons.
We found that a monokine induced by interferon-gamma (Mig, CXCL9), which belongs to the CXC chemokine subfamily, acts as a neurotrophic factor on PC12 cells and rat primary sympathetic neurons. PC12 cells were shown to express a single class of high affinity binding sites for Mig (670 receptors/cell, Kd = 2.9 nm). Mig induced neurite outgrowth in PC12 cells in a dose-dependent manner. Comparison of extracellular signal-regulated kinase signaling pathways between Mig and nerve growth factor (NGF) revealed that these pathways are crucial for Mig action as well as NGF. K252a, an inhibitor of tyrosine autophosphorylation of tyrosine kinase receptors (Trks) did not inhibit the action of Mig, suggesting that Mig action occurs via a different receptor from that of NGF. Furthermore, Mig as well as NGF promoted PC12 survival under serum-free conditions and activated Akt/protein kinase B downstream from phosphatidylinositol 3-kinase (PI3K). Because the PI3K inhibitor LY294002 prevented the Mig- and NGF-induced survival effect, this effect is probably mediated by the PI3K signaling pathway. Mig also promoted survival of rat primary sympathetic neurons that die when deprived of NGF. These results suggest that chemokines, including Mig (CXCL9) have neurotrophic effects on the nervous system.
Uwabe
Ken-Ichiro
K
Discovery Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. ken-ichiro.uwabe@shionogi.co.jp
Matsumoto
Mitsunobu
M
Nagata
Kiyoshi
K
D000818:Animals; D000906:Antibodies; D015153:Blotting, Western; D002454:Cell Differentiation; D002470:Cell Survival; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D018613:Microscopy, Confocal; D009414:Nerve Growth Factors / Q000502:physiology*; D016501:Neurites; D009474:Neurons; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013564:Sympathetic Nervous System
D000906:Antibodies; C505723:CXCL9 protein, rat; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D009414:Nerve Growth Factors; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases