Metallothionein-1+2 deficiency increases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin 6.
Transgenic expression of IL-6 under the control of the GFAP gene promoter (GFAP-IL6 mice) in the CNS causes significant damage and alters the expression of many genes, including the metallothionein (MT) family, especially in the cerebellum. The crossing of GFAP-IL6 mice with MT-1+2 knock out (MTKO) mice provided evidence that the increased MT-1+2 expression normally observed in the GFAP-IL6 mice is an important mechanism for coping with brain damage. Thus, the GFAP-IL6xMTKO mice showed a decreased body weight gain and an impaired performance in the rota-rod test, as well as a higher upregulation of cytokines such as IL-6, IL-1alpha,beta, and TNFalpha and recruitment and activation of macrophages and T cells throughout the CNS but mainly in the cerebellum. Clear symptoms of increased oxidative stress and apoptotic cell death caused by MT-1+2 deficiency were observed in the GFAP-IL6xMTKO mice. Interestingly, MT-1+2 deficiency also altered the expected frequency of the offspring genotypes, suggesting a role of these proteins during development. Overall, the results suggest that the MT-1+2 proteins are valuable factors against cytokine-induced CNS injury.
Giralt
Mercedes
M
Instituto de Neurociencías and Departamento de Biologia Celular, de Fisiología y de Immunología, Unidad de Fisiología Animal, Facultad de Ciencias, Universidad Autónoma de Barcelona, Bellaterra, Spain.
Penkowa
Milena
M
Hernández
Joaquín
J
Molinero
Amalia
A
Carrasco
Javier
J
Lago
Natalia
N
Camats
Jordi
J
Campbell
Iain L
IL
Hidalgo
Juan
J
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001923:Brain Chemistry / Q000235:genetics; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology
D005904:Glial Fibrillary Acidic Protein; D015850:Interleukin-6; D008668:Metallothionein