Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons.
Interleukin (IL)-6 expression transiently increases in the acute phase of cerebral ischemia. To investigate the physiological significance of endogenous IL-6 expression and to identify the main signal pathway for the action of IL-6, we administered anti-mouse IL-6 receptor monoclonal antibody (IL-6RA), which blocks IL-6 signaling, to mice immediately after a 45-min period of middle cerebral artery occlusion (MCAO). At 6 h after MCAO, IL-6RA administration had resulted in a significant reduction in the amount of phosphorylated signal transducer and activator of transcription-3 (Stat3) protein in the peri-infarct area of the cortex. At 24 h after MCAO, blockade of IL-6 signaling had led to an increase in number of apoptotic cells in the peri-infarct area and enlargement of the size of the infarct, and it had adversely affected neurological function. These results suggest that endogenous IL-6 plays a critical role in preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia and that its role may be mediated by Stat3 activation.
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
Toru
T
Yamashita
Kazunobu
K
Sawamoto
Shigeaki
S
Suzuki
Norihiro
N
Suzuki
Kazuhide
K
Adachi
Takeshi
T
Kawase
Masahiko
M
Mihara
Yoshiyuki
Y
Ohsugi
Koji
K
Abe
Hideyuki
H
Okano
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000166:cytology* / Q000473:pathology; D016009:Chi-Square Distribution; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006651:Histocytochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D053148:Caspase 3; D020169:Caspases; D004268:DNA-Binding Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D015850:Interleukin-6; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C505409:Casp3 protein, mouse