Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuates ischemic brain injury in rats.
Cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 is known to exert a neurotrophic action in the central nervous system, although the role of this signaling in cerebral ischemia remains unknown. We examined the effect of intracerebral injection of LIF after focal cerebral ischemia in rats. The animals underwent a sham operation (sham group) or middle cerebral artery occlusion (MCAO) followed by direct injection of either vehicle (phosphate-buffered saline, the PBS group) or recombinant LIF (10 ng in the low-LIF group and 100 ng in the high-LIF group) into the cerebral cortex adjacent to the inner boundary zone of the infarct area, and neurologic and histologic evaluations were conducted 24 h later. Expression of LIFR, gp130, and phosphorylated Stat3, Akt, and ERK1/2 was investigated by Western blot analysis and immunohistochemistry. The neurologic deficits and ischemic damage were significantly less severe in the high-LIF group than in the PBS group and the low-LIF group. Leukemia inhibitory factor receptor and gp130 were expressed in neurons, and the ischemic damage of these proteins was rescued in the high-LIF group. Early induction of phosphorylated Stat3 was significantly detected on the ischemic side in the high-LIF group after LIF injection. Exogenous LIF attenuates ischemic brain injury by activating cytokine signaling through LIFR/gp130.
Suzuki
Shigeaki
S
Department of Neurology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. Shigeaki714@aol.com
Yamashita
Toru
T
Tanaka
Kortaro
K
Hattori
Hidenori
H
Sawamoto
Kazunobu
K
Okano
Hideyuki
H
Suzuki
Norihiro
N
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D018121:Receptors, Cytokine / Q000378:metabolism*; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism
D015703:Antigens, CD; D016207:Cytokines; D004268:DNA-Binding Proteins; C494201:Il6st protein, rat; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3