Reduced Severity of Experimental Autoimmune Encephalomyelitis in GMF-Deficient Mice

Zaheer, Asgar; Zaheer, Smita; Sahu, Shailendra K.; Yang, Baoli; Lim, Ramón

doi:10.1007/s11064-006-9220-x

Cited by 33 publications

(56 citation statements)

References 41 publications

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“…We reported that the overexpression of GMF in astrocytes leads to the destruction of primary oligodendrocytes, the myelin-forming cells in the central nervous system, by interactions between astrocytes, microglia, and oligodendrocytes. These results suggested a novel pathway of GMF initiated cytotoxicity of brain cells, and implicated its involvement in the pathogenesis of inflammatory demyelinating diseases of the central nervous system such as multiple sclerosis/ experimental autoimmune encephalomyelitis (Menon et al, 2007;Zaheer et al, 2007a;Zaheer et al, 2007b;Zaheer et al, 2007c;Zaheer et al, 2007d). In the present report we show that the overexpression of GMF in neuroblastoma N18 cells directly induces caspase-dependent apoptosis mediated by GSK-3β activation.…”

Section: Introductionsupporting

confidence: 65%

“…The results also demonstrate that the increased release of GMF-dependent microglial proinflammatory cytokines is cytotoxic to oligodendrocytes, the myelin-forming cells of the central nervous system (Zaheer et al, 2007b). We described novel interactions of brain cells to produce the mediators of neurodegenerative diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) (Zaheer et al, 2007a;Zaheer et al, 2007b;Zaheer et al, 2007c).…”

Section: Discussionmentioning

confidence: 98%

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Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

et al. 2008

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In the present study we report that a replication-defective adenovirus construct of GMF cDNA (GMF-V) induced overexpression of GMF protein in neuroblastoma (N18) cells caused cytotoxicity and loss of cell viability. A significant increase in activation of GSK-3β occurred after infection with GMF-V when compared with mock and lacZ controls. Overexpression of GMF also increased caspase-3 activity, an early marker of apoptosis. Depletion of GMF gene by introducing GMFspecific siRNA (GsiRNA) completely blocked both activation of GSK-3β and caspase-3 activation whereas a control scrambled siRNA (CsiRNA) had no effect. A cell-permeable peptide inhibitor of GSK-3β, and lithium completely prevented GMF-dependent activation of caspase-3. These results demonstrate that GSK-3 mediates activation of the death domain caspase by GMF overexpression. We also show that the phosphorylation of GSK-3-dependent site of Tau was a consequence of GMFoverexpression in N18 cells. Taken together our results imply that GMF is involved in the signaling leading to the activation of GSK-3β and caspase-3 in N18 cells and strongly suggest its involvement in neurodegeneration since, GSK-3β is known to hyperphosphorylate tau which is associated with the neurotoxicity of neurofibrillary tangles in Alzheimer's disease. KeywordsGlia maturation factor (GMF); neuroblastoma (N18) cells; glycogen synthase kinase-3β (GSK-3β);

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 98%

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

et al. 2008

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“…Recent studies on glia maturation factor (GMF), a brain-specific protein, isolated, sequenced and cloned in our laboratory (Kaplan et al, 1991;Lim et al, 1989;Lim et al, 1990), have given new insights into its role in immunomodulatory and proinflammatory functions in CNS (Lim and Zaheer, 1996;Lim et al, 2000;Zaheer et al, 2002;Zaheer et al, 2004;Zaheer et al, 2006;Zaheer et al, 2007). We have established that overexpression of GMF in astrocytes leads to immune activation of microglia, through secretion of granulocyte-macrophage-colony stimulating factor (GM-CSF), and resulting in production of several pro inflammatory mediators that destroy oligodendrocytes, the myelin forming cells in CNS.…”

Section: Introductionmentioning

confidence: 99%

“…We hypothesize that intracellular GMF is involved in the pathogenesis of inflammatory diseases of the central nervous system such as MS and EAE. More recently, we have shown that GMF −/− mice (GMF-KO) were resistant to EAE induced by active immunization with MOG-35-55 antigen, whereas GMF +\+ (Wt) mice developed the disease characterized by significantly increased inflammation and demyelination in the central nervous system (Zaheer et al, 2007). In the present study, to analyze the inflammatory and immune mechanisms underlying the beneficiary effects of GMF deficiency in mice, we compared the development of EAE in wild type (Wt) and GMF-KO mice in both active and adoptive transfer models.…”

Section: Introductionmentioning

confidence: 99%

Diminished cytokine and chemokine expression in the central nervous system of GMF-deficient mice with experimental autoimmune encephalomyelitis

Zaheer¹,

Sahu

et al. 2007

Brain Research

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Pro-inflammatory cytokines/chemokines are implemented in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model with clinical and pathological similarities to multiple sclerosis. We have previously shown that over-expression of glia maturation factor (GMF) in glial cells cause excessive production and secretion of pro-inflammatory cytokines/chemokines sufficient to destroy the myelin forming oligodendroglial cell in-vitro. In this present investigation, we evaluate the expression of pro-inflammatory mediators in the central nervous system (CNS) of GMF+/+ (wild type) mice and GMF−/− (GMF-knockout) mice at the peak of EAE induced by immunization with MOG 35-55 peptide. GMF+/+ (Wt) mice developed severe EAE with a maximal mean clinical score of 3.6 ±0.5 by day 16 post immunization, whereas GMF-KO mice showed significantly delayed EAE with an average onset on day 26 pi with reduced mean clinical score of 1.3 ±0.3. Three of fifteen Wt mice as compared to none of GMF-KO mice died of EAE. Encephalitogenic cells from Wt mice transferred to recipient GMF-KO mice caused very mild and with low incidence of EAE. We determined the differences in the expression of cytokines, IFN-γ, TNF-α, IL-1 β, IL-6, IL-4, IL-10, and chemokines, MIP-1, MIP-2, IP-10, MCP-1, GM-CSF mRNA by quantitative real time RT-PCR in brain and spinal cord. Our results demonstrate significantly low levels of pro inflammatory cytokines/chemokines in the CNS of GMF-KO mice and increased expression in Wt mice with EAE. Our data suggest that GMF play a critical role in CNS inflammation.

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“…gMFβ is an intracellular protein that is primarily localized in the mammalian central nervous system and plays an important role in regulating the growth and development of glial cells and neurons. gMF is found to mediate apoptosis in glioblastoma cells as well as the development of inflammation (28)(29)(30). studies have suggested that gMF interacts with ADF/ cofilin to promote the remodeling and/or disassembly of brain cortical actin structures (31).…”

Section: Discussionmentioning

confidence: 99%

β-elemene inhibits proliferation of human glioblastoma cells through the activation of glia maturation factor β and induces sensitization to cisplatin

Zhu

Dong³

et al. 2011

Oncol Rep

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Abstract. β-elemene, a natural drug extracted from Curcuma wenyujin, strongly inhibits glioblastoma growth. However, the mechanism of β-elemene antitumor action remains unclear. glia maturation factor β (gMFβ) regulates cellular growth, fission, differentiation and apoptosis. It has been reported that overexpression of GMFβ inhibits the growth of glioblastoma cells and decreases tumor volume. to illustrate the role of gMFβ in the anti-proliferative effect of β-elemene in glioblastoma, U87 cells were treated with β-elemene at various doses and for different periods of time, and levels of phospho-gMFβ (p-gMFβ) and total gMFβ were determined by immunoprecipitation and western blot analysis. Upon gMFβ silencing using rnA interference, the antitumor action of β-elemene was evaluated in a methyl thiazolyl tetrazolium assay and by semi-quantitative western blot analysis of MKK3/6 and p-MKK3/6 expression. Finally, chemosensitization to cisplatin by β-elemene was examined using a cell counting array, and the cell growth inhibitory rate was calculated. the results showed that β-elemene inhibits U87 cell viability through the activation of the gMFβ signaling pathway. conversely, silencing the expression of gMFβ reversed the antitumor effect of β-elemene and impaired the phosphorylation of MKK3/6. Furthermore, β-elemene increased the sensitivity of U87 glioblastoma cells to the chemotherapeutic agent cisplatin. taken together, these results suggest that activation of the gMFβ pathway mediates the antitumor effect of β-elemene in glioblastoma. gMFβ is a putative molecular target for glioblastoma therapy.

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Reduced Severity of Experimental Autoimmune Encephalomyelitis in GMF-Deficient Mice

Cited by 33 publications

References 41 publications

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

Glia maturation factor overexpression in neuroblastoma cells activates glycogen synthase kinase-3β and caspase-3

Diminished cytokine and chemokine expression in the central nervous system of GMF-deficient mice with experimental autoimmune encephalomyelitis

β-elemene inhibits proliferation of human glioblastoma cells through the activation of glia maturation factor β and induces sensitization to cisplatin

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