Dataset Information

Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK.

ABSTRACT:

Background

Programmed cell death of motoneurons in the developing spinal cord is thought to be regulated through the availability of target-derived neurotrophic factors. When deprived of trophic support, embryonic spinal motoneurons in vitro over-express FasL, a ligand activating a Fas-mediated death pathway. How trophic factors regulate the expression of FasL is presently unclear, but two regulators of FasL, FOXO3a (FKHRL1) and JNK have been described to play a role in other cell types. Thus, their potential function in motoneurons was investigated in this study.

Results

We show here that as a result of removal of neurotrophic factors and the consequent reduction in signalling through the PI3K/Akt pathway, Foxo3a translocates from the cytoplasm to the nucleus where it triggers cell death. Death is reduced in Fas and FasL mutant motoneurons and in the presence of JNK inhibitors indicating that a significant part of it requires activation of the Fas/FasL pathway through JNK.

Conclusions

Therefore, in motoneurons as in other cell types, FOXO transcriptional regulators provide an important link between other signalling pathways and the cell death machinery.

SUBMITTER: Barthelemy C

PROVIDER: S-EPMC538283 | biostudies-literature | 2004 Nov

REPOSITORIES: biostudies-literature

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Publications

Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK.

Barthélémy Catherine C Henderson Christopher E CE Pettmann Brigitte B

BMC neuroscience 20041129

<h4>Background</h4>Programmed cell death of motoneurons in the developing spinal cord is thought to be regulated through the availability of target-derived neurotrophic factors. When deprived of trophic support, embryonic spinal motoneurons in vitro over-express FasL, a ligand activating a Fas-mediated death pathway. How trophic factors regulate the expression of FasL is presently unclear, but two regulators of FasL, FOXO3a (FKHRL1) and JNK have been described to play a role in other cell types. ...[more]

PMID: 15569384

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Project description:BackgroundIntestinal ischemia is a common clinical critical illness. Intestinal ischemia-reperfusion (IIR) leads to acute lung injury (ALI), but the causative factors of ALI are unknown. The aim of this study was to reveal the causative factors and mechanisms of IIR-induced lung injury.MethodsA mouse model of IIR was developed using C57BL/6 mice, followed by detection of lung injury status and plasma levels of inflammatory factors in sham-operated mice and model mice. Some model mice were treated with a tumor necrosis factor-α (TNF-α) inhibitor lenalidomide (10 mg/kg), followed by observation of lung injury status through hematoxylin and eosin staining and detection of neutrophil infiltration levels through naphthol esterase and Ly6G immunohistochemical staining. Additionally, peripheral blood polymorphonuclear neutrophils (PMNs) were cultured in vitro and then stimulated by TNF-α to mimic in vivo inflammatory stimuli; this TNF-α stimulation was also performed on PMNs after knockdown of FoxO3a or treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. PMN apoptosis after stimulation was detected using flow cytometry. Finally, the role of PMN apoptosis in IIR-induced lung injury was evaluated in vivo by detecting the ALI status in the model mice administered with ABT-199, a Bcl-2 inhibitor.ResultsIIR led to pulmonary histopathological injury and increased lung water content, which were accompanied by increased plasma levels of inflammatory factors, with the TNF-α plasma level showing the most pronounced increase. Inhibition of TNF-α led to effective reduction of lung tissue injury, especially that of the damaging infiltration of PMNs in the lung. In vitro knockdown of FoxO3a or inhibition of JNK activity could inhibit TNF-α-induced PMN apoptosis. Further in vivo experiments revealed that ABT-199 effectively alleviated lung injury and decreased inflammation levels by promoting PMN apoptosis during IIR-induced lung injury.ConclusionTNF-α activates the JNK/FoxO3a pathway to induce a delay in PMN apoptosis, which promotes IIR-induced lung injury.

Dataset Information

Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK.

Background

Results

Conclusions

Publications

Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK.

Similar Datasets

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