title: Metallothionein-I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte-targeted interleukin-6 expression.
abstract: Transgenic expression of IL-6 in the CNS under the control of the GFAP gene promoter, glial fibrillary acidic protein-interleukin-6 (GFAP-IL-6) mice, raises an inflammatory response and causes significant brain damage. However, the results obtained in the GFAP-IL-6 mice after a traumatic brain injury, such as a cryolesion, demonstrate a neuroprotective role of IL-6. Thus, the GFAP-IL-6 mice showed faster tissue repair and decreased oxidative stress and apoptosis compared with control litter-mate mice. The neuroprotective factors metallothionein-I+II (MT-I+II) were upregulated by the cryolesion to a higher extent in the GFAP-IL-6 mice, suggesting that they could be related to the neuroprotection afforded by the transgenic expression of IL-6. To examine this possibility, we have crossed GFAP-IL-6 mice with transgenic mice overexpressing MT-I (TgMT), producing double transgenic GFAP-IL-6 TgMT mice. The results obtained after cryolesion in GFAP-IL-6 TgMT mice, as well as in TgMT mice, consistently supported the idea that the increased MT-I+II levels observed in GFAP-IL-6 mice are a fundamental and important mechanism for coping with brain damage. Accordingly, MT-I overexpression regulated the inflammatory response, decreased oxidative stress and apoptosis significantly, and increased brain tissue repair in comparison with either GFAP-IL-6 or control litter-mate mice. Overall, the results demonstrate that brain MT-I+II proteins are fundamental neuroprotective factors.
authors.affiliation: Department of Medical Anatomy, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Milena
authors.initials: M
authors.lastname: Penkowa
authors.forename: Jordi
authors.initials: J
authors.lastname: Camats
authors.forename: Mercedes
authors.initials: M
authors.lastname: Giralt
authors.forename: Amalia
authors.initials: A
authors.lastname: Molinero
authors.forename: Joaquín
authors.initials: J
authors.lastname: Hernández
authors.forename: Javier
authors.initials: J
authors.lastname: Carrasco
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation / Q000235:genetics; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005911:Gliosis / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D008668:Metallothionein