Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons

J Neurochem. 2005 Jul;94(2):459-68. doi: 10.1111/j.1471-4159.2005.03227.x.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects
  • Behavior, Animal
  • Blotting, Western / methods
  • Brain Ischemia / etiology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Caspase 3
  • Caspases / metabolism
  • Cell Count / methods
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / pathology
  • Chi-Square Distribution
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / drug effects
  • Enzyme-Linked Immunosorbent Assay / methods
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Histocytochemistry / methods
  • Infarction, Middle Cerebral Artery / complications
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons / drug effects*
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger / metabolism
  • Receptors, Interleukin-6 / antagonists & inhibitors
  • Receptors, Interleukin-6 / immunology
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • STAT3 Transcription Factor
  • Signal Transduction / drug effects
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Time Factors
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Antibodies, Monoclonal
  • DNA-Binding Proteins
  • Interleukin-6
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Interleukin-6
  • Repressor Proteins
  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases