In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice.
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 IL1beta 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-alpha, interferon-gamma, and IL1beta. 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.
de Bilbao
Fabienne
F
Department of Psychiatry, University Hospitals of Geneva, Belle-Idée, Geneva, Switzerland.
Arsenijevic
Denis
D
Moll
Thomas
T
Garcia-Gabay
Irene
I
Vallet
Philippe
P
Langhans
Wolfgang
W
Giannakopoulos
Panteleimon
P
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020520:Brain Infarction / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D002545:Brain Ischemia / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D004660:Encephalitis / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D042783:Endothelial Cells / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005978:Glutathione / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D016207:Cytokines; D018836:Inflammation Mediators; D016753:Interleukin-10; D020932:Nerve Growth Factor; D053148:Caspase 3; D005978:Glutathione