Interleukin-1 stimulates glutamate uptake in glial cells by accelerating membrane trafficking of Na+/K+-ATPase via actin depolymerization.
Interleukin-1 (IL-1) is a mediator of brain injury induced by ischemia, trauma, and chronic neurodegenerative disease. IL-1 also has a protective role by preventing neuronal cell death from glutamate neurotoxicity. However, the cellular mechanisms of IL-1 action remain unresolved. In the mammalian retina, glutamate/aspartate transporter (GLAST) is a Na(+)-dependent, major glutamate transporter localized to Müller glial cells, and loss of GLAST leads to glaucomatous retinal degeneration (T. Harada, C. Harada, K. Nakamura, H. A. Quah, A. Okumura, K. Namekata, T. Saeki, M. Aihara, H. Yoshida, A. Mitani, and K. Tanaka, J. Clin. Investig. 117:1763-1770, 2007). We show here that IL-1 increases glutamate uptake in Müller cells by a mechanism that involves increased membrane Na(+)/K(+)-ATPase localization, required for counteracting the Na(+)-glutamate cotransport. IL-1 activated the p38 mitogen-activated protein kinase (MAPK)/capase 11 pathway, which destabilizes the actin cytoskeleton allowing Na(+)/K(+)-ATPase membrane redistribution. Furthermore, pretreatment with IL-1 protected retinal neurons from glutamate neurotoxicity through p38 MAPK signaling. Our observations suggested that IL-1 acts as a potential neuroprotective agent by modulating the functions of the glia-neuron network.
Namekata
Kazuhiko
K
Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan.
Harada
Chikako
C
Kohyama
Kuniko
K
Matsumoto
Yoh
Y
Harada
Takayuki
T
D000199:Actins / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001693:Biological Transport, Active / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics; D053471:Caspases, Initiator; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism*; D034622:RNA Interference; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012162:Retinal Degeneration / Q000517:prevention & control; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D000199:Actins; D061945:Caspase Inhibitors; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D018698:Glutamic Acid; D012964:Sodium; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D000254:Sodium-Potassium-Exchanging ATPase