Metallothionein-1+2 Deficiency Increases Brain Pathology in Transgenic Mice with Astrocyte-Targeted Expression of Interleukin 6

Giralt, Mercedes; Penkowa, Milena; Hernández, Jesús Avilla; Molinero, Amalia; Carrasco, Javier; Lago, Natalia; Camats, Jordi; Campbell, Iain L.; Hidalgo, Juan

doi:10.1006/nbdi.2002.0480

Cited by 57 publications

(51 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These genes were reanalyzed by MANOVA, and a subsequent decomposition of interaction was performed, showing the number of genes affected by cryolesion in each genotype and the combination of both (A) and the number of genes affected by cryolesion at each time point studied (B). A complete gene list can be found in Supplementary Astrocyte-Targeted IL-6 Production Enhances Inflammatory Response After Injury IL-6 has been widely described as a proinflammatory cytokine (Muñoz-Fernández and Fresno, 1998;Van Wagoner and Benveniste, 1999) and in this regard GFAP-IL6 mice have been extensively described to produce spontaneous neuroinflammation (Campbell et al, 1993;Giralt et al, 2002). Activation of microglia/macrophages is part of the phenotype of the GFAP-IL6 mice (Campbell et al, 1993), and it has been shown to be higher than in control mice up to 6 Figure 3 Hierarchical clustering of the 329 genes identified to be significantly (p < 0.05) affected by the cryolesion only.…”

Section: Gene Selection and Functional Analysismentioning

confidence: 99%

“…Depending on the injury model, IL6 KO animals show a compromised inflammatory response, gliosis, and specific neuronal survival (Kopf et al, 1994;Penkowa et al, 1999;Murphy et al, 2000;Swartz et al, 2001;Poulsen et al, 2005). On the other hand, transgenic production of IL-6 under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) induces neuroinflammation (Campbell et al, 1993;Chiang et al, 1994;Brett et al, 1995;Giralt et al, 2002) and learning impairments (Steffensen et al, 1994;Heyser et al, 1997). However, when an acute injury is superimposed, elevated IL-6 levels lead to increased CNS repair with decreased cell death (Swartz et al, 2001;Penkowa et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of astrocyte‐targeted production of IL‐6 on traumatic brain injury and its impact on the cortical transcriptome

Quintana

Molinero

Borup

et al. 2007

Developmental Neurobiology

Self Cite

View full text Add to dashboard Cite

Interleukin-6 (IL-6) is one of the key players in the response of the brain cortex to injury. We have described previously that astrocyte-driven production of IL-6 (GFAP-IL6) in transgenic mice, although causing spontaneous neuroinflammation and long term damage, is beneficial after an acute (freeze) injury in the cortex, increasing healing and decreasing oxidative stress and apoptosis. To determine the transcriptional basis for these responses here we analyzed the global gene expression profile of the cortex, at 0 (unlesioned), 1 or 4 days post lesion (dpl), in both GFAP-IL6 mice and their control littermates. GFAP-IL6 mice showed an increase in genes associated with the inflammatory response both at 1 dpl (Iftm1, Endod1) and 4 dpl (Gfap, C4b), decreased expression of proapoptotic genes (i.e. Gadd45b, Clic4, p21) as well as reduced expression of genes involved in the control of oxidative stress (Atf4). Furthermore, the presence of IL-6 altered the expression of genes involved in hemostasis (Vwf), cell migration and proliferation (Cap2), and synaptic activity (Vamp2). All these changes in gene expression could underlie the phenotype of the GFAP-IL6 mice after injury, but many other possible factors were also identified in this study, highlighting the utility of this approach for deciphering new pathways orchestrated by IL-6.

show abstract

Section: Gene Selection and Functional Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of astrocyte‐targeted production of IL‐6 on traumatic brain injury and its impact on the cortical transcriptome

Quintana

Molinero

Borup

et al. 2007

Developmental Neurobiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In accordance, the opposite was observed in MT-1&2-null mice (98), pointing to an essential role of MT-1&2 in coping with ischemic damage of the brain. Other studies with transgenic mice have equally involved MT-1&2 as important proteins following damage elicited by kainic acid-induced seizures (94), gliotoxins (105, 122), 6-hydroxydopamine (123), amyotrophic lateral sclerosis (38, 100), multiple sclerosis (103,124), traumatic brain injury (28,125,126), and transgenic IL-6-induced neuropathology (127)(128)(129). All of the above are presumably quite different models of brain injury, yet the general impression is that MT-1&2 have similar effects in all cases, namely, decreasing oxidative stress, inflammation and apoptosis in the CNS.…”

Section: Transgenic Mice Show That Metallothionein-1and2 Are Essential mentioning

confidence: 99%

Metallothioneins and brain injury: What transgenic mice tell us

Hidalgo

2004

Environ Health Prev Med

Self Cite

View full text Add to dashboard Cite

In rodents, the metallothionein (MT) family is composed of four members, MT-1 to MT-4. MT-1&2 are expressed in virtually all tissues including those of the Central Nervous System (CNS), while MT-3 (also called Growth Inhibitory Factor) and MT-4 are expressed prominently in the brain and in keratinizing epithelia, respectively. For the understanding of the physiological functions of these proteins in the brain, the use of transgenic mice has provided essential information. Results obtained in MT-1&2-null mice and in MT-1-overexpressing mice strongly suggest that these MT isoforms are important antioxidant, anti-inflammatory and antiapoptotic proteins in the brain. Results in MT-3-null mice show a very different pattern, with no support for MT-1&2-like functions. Rather, MT-3 could be involved in neuronal sprouting and survival. Results obtained in a model of peripheral nervous system injury also suggest that MT-3 could be involved in the control of nerve growth.

show abstract

“…This MT-IϩII increase is likely a protective, physiological response elicited in the brain for coping with IL-6-induced tissue injury. Indeed, genetic MT-IϩII deficiency increased brain pathology significantly in the GFAP-IL-6 mice (Giralt et al, 2002b).…”

Section: Introductionmentioning

confidence: 98%

Metallothionein‐I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte‐targeted interleukin‐6 expression

Penkowa¹,

Camats²,

Giralt³

et al. 2003

Glia

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Metallothionein-1+2 Deficiency Increases Brain Pathology in Transgenic Mice with Astrocyte-Targeted Expression of Interleukin 6

Cited by 57 publications

References 83 publications

Effect of astrocyte‐targeted production of IL‐6 on traumatic brain injury and its impact on the cortical transcriptome

Effect of astrocyte‐targeted production of IL‐6 on traumatic brain injury and its impact on the cortical transcriptome

Metallothioneins and brain injury: What transgenic mice tell us

Metallothionein‐I overexpression alters brain inflammation and stimulates brain repair in transgenic mice with astrocyte‐targeted interleukin‐6 expression

Contact Info

Product

Resources

About