In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice

• Published in: Journal of neurochemistry Vol. 110; no. 1; pp. 12 - 22
• Main Authors: de Bilbao, Fabienne, Arsenijevic, Denis, Moll, Thomas, Garcia-Gabay, Irene, Vallet, Philippe, Langhans, Wolfgang, Giannakopoulos, Panteleimon
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01-07-2009; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: Animals; Apoptosis - genetics; Biochemistry; Biological and medical sciences; Brain; Brain Infarction - genetics; Brain Infarction - immunology; Brain Infarction - therapy; Brain Ischemia - genetics; Brain Ischemia - immunology; Brain Ischemia - therapy; Caspase 3 - metabolism; Cytokines; Cytokines - metabolism; Down-Regulation - genetics; Encephalitis - genetics; Encephalitis - immunology; Encephalitis - therapy; Endothelial Cells - metabolism; Fundamental and applied biological sciences. Psychology; Genetic Therapy - methods; glia; glutathione; Glutathione - metabolism; Inflammation Mediators - metabolism; interleukin-10; Interleukin-10 - genetics; Ischemia; Isolated neuron and nerve. Neuroglia; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia - metabolism; middle cerebral artery occlusion; nerve growth factor; Nerve Growth Factor - metabolism; Neurology; Oxidation-Reduction; Oxidative Stress - genetics; Promoter Regions, Genetic - genetics; Rodents; Up-Regulation - genetics; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs; Endothelial cell; Infarct; Neuroglia; glutathione; Central nervous system; Cardiovascular disease; Nerve growth factor; Cerebral artery; glia; interleukin-10; Encephalon; Vascular disease; cytokines; Cerebrovascular disease; Nervous system diseases; Enzyme; Rodentia; Cytokine; Caspase; Astrocyte; Cerebral disorder; Microglia; Resistance; Peptidases; Vertebrata; Chronic; Mammalia; Mouse; Central nervous system disease; Interleukin 10; Brain ischemia; Hydrolases; Circulatory system; Artery occlusion; middle cerebral artery occlusion
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2009.06098.x

Early studies showed that the administration of the anti-inflammatory cytokine interleukin-10 (IL10) protects against permanent middle cerebral artery occlusion (MCAO) in mice. In this study, transgenic mice expressing murine IL10 (IL10T) directed by the major histocompatibility complex Ea promoter were produced and used to explore the effect of chronically increased IL10 levels on MCAO-related molecular mechanisms. IL10 was over-expressed in astrocytes, microglia, and endothelial brain cells in IL10T compared with wild type mice. Four days following MCAO, IL10T mice showed a 40% reduction in infarct size which was associated to significantly reduced levels of active caspase 3 compared with wild type mice. Under basal conditions, anti-inflammatory factors such as nerve growth factor and GSH were up-regulated and the pro-inflammatory cytokine IL1β was down-regulated in the brain of IL10T animals. In addition, these mice displayed increased basal GSH levels in microglial and endothelial cells as well as a marked increase in manganese superoxide dismutase in endothelial lining blood vessels. Following ischemia, IL10T mice showed a marked reduction in pro-inflammatory cytokines, including tumor necrosis factor-α, interferon-γ, and IL1β. Our data indicate that constitutive IL10 over-expression is associated with a striking resistance to cerebral ischemia that may be attributed to changes in the basal redox properties of glial/endothelial cells.