Nerve Growth Factor Protects Oligodendrocytes from Tumor Necrosis Factor-α-induced Injury through Akt-mediated Signaling Mechanisms

Takano, Ryosuke; Hisahara, Shin; Namikawa, Kazuhiko; Kiyama, Hiroshi; Okano, Hideyuki; Miura, Masayuki

doi:10.1074/jbc.m910419199

Cited by 45 publications

(34 citation statements)

References 92 publications

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“…Ras was shown to be required for the mitogenic response, but not the survival response . The survival response has been shown to be mediated via the Akt pathway (Ding et al, 2000;Takano et al, 2000). Thus the expression of Gas6 in spinal motor neurons, dorsal root ganglion neurons, and in developing embryos supports a role for Gas6/Axl in nervous system development and repair after spinal cord injury (Li et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

et al. 2003

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Microarray analysis revealed that transcripts for the Axl and Mer receptor tyrosine kinases are expressed at high levels in O4 ϩ -immunopanned oligodendrocytes isolated from second trimester human fetal spinal cord. In humans the sole known ligand for the Axl/Rse/Mer kinases is growth arrest-specific gene 6 (Gas6), which in the CNS is secreted by neurons and endothelial cells. We hypothesized that Gas6 is a survival factor for oligodendrocytes and receptor activation signals downstream to the phosphatidylinositol 3 (PI3)-kinase/Akt pathway to increase cell survival in the absence of cell proliferation. To test this hypothesis, we grew enriched human oligodendrocytes for 6 d on a monolayer of NIH3T3 cells stably expressing Gas6. CNP ϩ oligodendrocytes on Gas6-secreting 3T3 cells had more primary processes and arborizations than those plated solely on 3T3 cells. Also, a twofold increase in CNP ϩ and MBP ϩ oligodendrocytes was observed when they were plated on the Gas6-secreting cells. The effect was abolished in the presence of Axl-Fc but remained unchanged in the presence of the irrelevant receptor fusion molecule TrkA-Fc. A significant decrease in CNP ϩ /TUNEL ϩ oligodendrocytes was observed when recombinant human Gas6 (rhGas6) was administered to oligodendrocytes plated on poly-L-lysine, supporting a role for Gas6 signaling in oligodendrocyte survival during a period of active myelination in human fetal spinal cord development. PI3-kinase inhibitors blocked the anti-apoptotic effect of rhGas6, whereas a MEK/ERK inhibitor had no effect. Thus Gas6 sustains human fetal oligodendrocyte viability by receptor activation and downstream signaling via the PI3-kinase/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

et al. 2003

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“…In fact, many reports indicate that NGF has the ability to promote cell death in specific cell types such as developing retina neurons (40) and oligodendrocytes through the p75 NTR (41). There are other reports that NGF can protect breast cancer cells (42), monocytes, oligodendrocytes (43), and schwannoma cells (44) from death induction through activating NF-B via p75…”

Section: Discussionmentioning

confidence: 99%

Nerve Growth Factor Promotes TLR4 Signaling-Induced Maturation of Human Dendritic Cells In Vitro through Inducible p75NTR 1

Jiang

Chen

Zhang

et al. 2007

The Journal of Immunology

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Nerve growth factor (NGF) has been shown to play important roles in the differentiation, function, and survival of immune cells, contributing to immune responses and pathogenesis of autoimmune diseases. Dendritic cells (DCs) are a potent initiator for immune and inflammatory responses upon recognition of pathogens via Toll-like receptors (TLR). However, expression of NGF and its receptors on human monocyte-derived DCs (MoDCs) and the role of NGF in the response of DCs to TLR ligands remain to be investigated. In the present study, we demonstrate that there were weak expressions of NGF and no expression of NGF receptors p140TrkA and p75NTR on human immature MoDCs, however, the expression of NGF and p75NTR on MoDCs could be significantly up-regulated by LPS in a dose- and time-dependent manner. NGF could markedly promote LPS-induced expression of HLA-DR, CD40, CD80, CD83, CD86, CCR7, secretion of IL-12p40 and proinflammatory cytokines IL-1, IL-6, TNF-α, and the T cell-stimulating capacity of MoDCs, indicating that NGF can promote LPS-induced DC maturation. The promoting effect of NGF on LPS-induced MoDCs maturation could be completely abolished by pretreatment of MoDCs with p75NTR antagonist, suggesting that LPS-induced p75NTR mediates the effect. Furthermore, increased activation of the p38MAPK and NF-κB pathways has been shown to be responsible for the NGF-promoted DC maturation. Therefore, NGF facilitates TLR4 signaling-induced maturation of human DCs through LPS-up-regulated p75NTR via activation of p38 MAPK and NF-κB pathways, providing another mechanism for the involvement of NGF in the immune responses and pathogenesis of autoimmune diseases.

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“…Thus, it may be reasonable to speculate that the proapoptotic effect of IEX-1S is mediated by the inhibition of antiapoptotic signal(s) activated by TNF-␣. In several types of cells such as HeLa cells and human endothelial cells, TNF-␣ appears to activate serine/threonine kinase Akt via PI3K (28, 34 -36), which protects cells from apoptosis (28,29,36,37). In hepatocytes, TNF-␣ activates the PI3K/Akt pathway which inhibits apoptosis mediated by TNF-␣ and this protective effect is independent of NF-B (8).…”

Section: Discussionmentioning

confidence: 99%

“…We then hypothesized that IEX-1S inhibits the antiapoptotic signaling induced by TNF-␣. Activation of Akt via PI3K has been reported to protect cells from apoptosis induced by TNF-␣ (8,28,29). Bcl-2 family members have been documented to play a central role in regulating the apoptotic process (30).…”

Section: Effects Of Overexpressed Iex-1s On Activation Of Pi3k/akt Anmentioning

confidence: 99%

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Osawa

Nagaki

Banno

et al. 2003

The Journal of Immunology

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Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-α and also depend on NF-κB activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF-α-induced apoptosis in Hc cells expressing a mutant form of IκB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF-α-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF-α and accelerated TNF-α-induced apoptosis in IκB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF-α-induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-κB-dependent recruitment of IEX-1S may play a proapoptotic role in TNF-α-stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF-α-induced hepatocyte apoptosis.

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Nerve Growth Factor Protects Oligodendrocytes from Tumor Necrosis Factor-α-induced Injury through Akt-mediated Signaling Mechanisms

Cited by 45 publications

References 92 publications

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

TheGrowth Arrest-SpecificGene Product Gas6 Promotes the Survival of Human Oligodendrocytes via a Phosphatidylinositol 3-Kinase-Dependent Pathway

Nerve Growth Factor Promotes TLR4 Signaling-Induced Maturation of Human Dendritic Cells In Vitro through Inducible p75NTR 1

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

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