Metallothionein-I Overexpression Decreases Brain Pathology in Transgenic Mice with Astrocyte-Targeted Expression of Interleukin-6

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

doi:10.1093/jnen/62.3.315

Cited by 38 publications

(46 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, an up-regulation of the metallothionein-I gene in brain, heart, and liver by IL-6 has been reported previously. 61,62 However, three lines of evidence suggest that the impaired tumor growth in the MT-ret ϩ/Ϫ /IL-6 Ϫ/Ϫ mice cannot be explained by a decrease of MT-ret transgene expression because of lack of IL-6. First, Ret protein expression levels measured by immunoblotting were not decreased in the skin of MTret ϩ/Ϫ /IL-6 Ϫ/Ϫ compared to MT-ret ϩ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Felbert

Córdoba

Weissenberger

et al. 2005

The American Journal of Pathology

View full text Add to dashboard Cite

Interleukin (IL)-6 is a pleiotropic cytokine that has been shown to inhibit the growth of early stage and to promote the proliferation of advanced stage melanoma cells in vitro. In patients with metastasizing melanomas, highly increased IL-6 blood levels correlate with a poor response to chemotherapy and a worse overall prognosis, suggesting that IL-6 promotes melanoma progression in vivo. Here, we analyzed the role of IL-6 in melanoma development and progression in a transgenic mouse model. We bred IL-6-deficient mice with MT-ret transgenic animals predisposed for melanomas. While MT-ret transgenic animals develop severe melanosis of the skin and subcutis and subsequent melanomas at an incidence of 80% during their first year of life, MT-ret mice devoid of IL-6 developed preneoplastic melanosis and consecutive melanomas significantly less frequently (47%; P < 0.05). Moreover, the tumors were significantly smaller in the groups of MT-ret mice lacking one (P < 0.05) or both (P < 0.01) copies of the IL-6 gene. Immunoblot analysis revealed that ret transgene expression was not reduced in the skin of mice lacking IL-6, indicating that the observed decrease of melanoma incidence and of tumor sizes was not because of a down-regulation of transgene expression. Interleukin (IL)-6 is a pleiotropic cytokine that induces the acute phase response, stimulates B-and T-lymphocytes, and regulates the growth, differentiation, and death of several cell populations including neurons and melanocytes. 1-3 IL-6 promotes the development and progression of plasmacytomas 4 and gliomas 4,5 in vivo. It is also a growth-promoting factor for human basal cell carcinoma, Kaposi's sarcoma, and prostate cancer cells in vitro. 3,6 The IL-6 receptor system consists of IL-6 receptor ␣ (IL-6R␣), the primary IL-6 receptor, and the ubiquitous gp130 signal-transducing receptor subunit. Binding of IL-6 to its receptor complex leads to the activation of janus kinases (Jaks) and subsequent phosphorylation, dimerization, and nuclear translocation of signal transducer and activator of transcription 3 (STAT3). 2,7 STAT3 promotes tumor progression by regulating the expression of genes involved in growth control such as c-myc, antiapoptosis [Bcl-x(L) and Mcl-1] and angiogenesis (vascular endothelial growth factor). 8 -11 In a recent study, STAT3 was found to be constitutively activated in some, but not all human melanoma cell lines and tumor specimens analyzed. 12 However, blocking experiments revealed that STAT3 activation in these cell lines was apparently mainly caused by Src tyrosine kinase activity and not by Jak activation. 12

show abstract

Section: Discussionmentioning

confidence: 99%

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Felbert

Córdoba

Weissenberger

et al. 2005

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…To this end, we have used a cryolesion procedure and have taken advantage of transgenic mice in which either the type I or the type II receptor of TNF-a has been knocked out. As stated above, we have used this cryolesion procedure extensively, in studies in which a major role of another cytokine, IL-6, was demonstrated (Penkowa et al, 1999(Penkowa et al, , 2000aMolinero et al, 2003;Poulsen et al, 2005). Cytokines often show overlapping effects, and, not surprisingly, IL-6 could not account for all the effects of the inflammatory response caused by cryolesion, suggesting that other factors might be involved in the control of these responses.…”

Section: Roles Of Tnf-a Receptors In Response To Brain Injury Are DIVmentioning

confidence: 99%

Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

Quintana

Giralt

Rojas

et al. 2005

J of Neuroscience Research

Self Cite

View full text Add to dashboard Cite

Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracellular signaling. This cytokine exerts its functions via interaction with two receptors: type-1 receptor (TNFR1) and type-2 receptor (TNFR2). In this work, the inflammatory response after a freeze injury (cryolesion) in the cortex was studied in wild-type (WT) animals and in mice lacking TNFR1 (TNFR1 KO) or TNFR2 (TNFR2 KO). Lack of TNFR1, but not of TNFR2, significantly decreased the inflammatory response and tissue damage elicited by the cryolesion at both 3 and 7 days postlesion, with decreased gliosis, lower IL-1beta immunostaining, and a reduction of apoptosis markers. Cryolesion produced a clear induction of the proinflammatory cytokines interleukin (IL)-1alpha, IL-1beta, IL-6, and TNF-alpha; this induction was significantly lower in the TNFR1 KO mice. Host response genes (ICAM-1, A20, EB22/5, and GFAP) were also induced by the cryolesion, but to a lesser extent in TNFR1 KO mice. Lack of TNFR1 signaling also affected the expression of apoptosis/cell death-related genes (Fas, Rip, p53), matrix metalloproteinases (MMP3, MMP9, MMP12), and their inhibitors (TIMP1), suggesting a role of TNFR1 in extracellular matrix remodeling after injury. However, GDNF, NGF, and BDNF expression were not affected by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury.

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

Metallothionein-I Overexpression Decreases Brain Pathology in Transgenic Mice with Astrocyte-Targeted Expression of Interleukin-6

Cited by 38 publications

References 69 publications

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Interleukin-6 Gene Ablation in a Transgenic Mouse Model of Malignant Skin Melanoma

Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

Metallothioneins and brain injury: What transgenic mice tell us

Contact Info

Product

Resources

About