| TNFalpha-induced glutathione depletion lies downstream of cPLA(2) in L929 cells. | |
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MedLine Citation:
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PMID: 11684089 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Both glutathione (GSH) depletion and arachidonic acid (AA) generation have been shown to regulate sphingomyelin (SM) hydrolysis and are known components in tumor necrosis factor alpha (TNFalpha)-induced cell death. In addition, both have hypothesized direct roles in activation of N-sphingomyelinase (SMase); however, it is not known whether these are independent pathways of N-SMase regulation or linked components of a single ordered pathway. This study was aimed at differentiating these possibilities using L929 cells. Depletion of GSH with L-buthionin-(S,R)-sulfoximine (BSO) induced 50% hydrolysis of SM at 12 h. In addition, TNF induced a depletion of GSH, and exogenous addition of GSH blocked TNF-induced SM hydrolysis as well as TNF-induced cell death. Together, these results establish GSH upstream of SM hydrolysis and ceramide generation in L929 cells. We next analyzed the L929 variant, C12, which lacks both cytosolic phospholipase A(2) (cPLA(2)) mRNA and protein, in order to determine the relationship of cPLA(2) and GSH. TNF did not induce a significant drop in GSH levels in the C12 line. On the other hand, AA alone was capable of inducing a 60% depletion of GSH in C12 cells, suggesting that these cells remain responsive to AA distal to the site of cPLA(2). Furthermore, depleting GSH with BSO failed to effect AA release, but caused a drop in SM levels, showing that the defect in these cells was upstream of the GSH drop and SMase activation. When cPLA(2) was restored to the C12 line by expression of the cDNA, the resulting CPL4 cells regained sensitivity to TNF. Treatment of the CPL4 cells with TNF resulted in GSH levels dropping to levels near those of the wild-type L929 cells. These results demonstrate that GSH depletion following TNF treatment in L929 cells is dependent on intact cPLA(2) activity, and suggest a pathway in which activation of cPLA(2) is required for the oxidation and reduction of GSH levels followed by activation of SMases. |
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Authors:
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H L Hayter; B J Pettus; F Ito; L M Obeid; Y A Hannun |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: FEBS letters Volume: 507 ISSN: 0014-5793 ISO Abbreviation: FEBS Lett. Publication Date: 2001 Oct |
Date Detail:
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Created Date: 2001-10-30 Completed Date: 2001-12-11 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0155157 Medline TA: FEBS Lett Country: Netherlands |
Other Details:
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Languages: eng Pagination: 151-6 Citation Subset: IM |
Affiliation:
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Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Buthionine Sulfoximine / metabolism Cell Line Cell Survival Ceramides / metabolism Cytosol / enzymology Glutathione / metabolism* Hydrolysis Mice Phospholipases A / genetics, metabolism* Sphingomyelin Phosphodiesterase / metabolism Tumor Necrosis Factor-alpha / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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AG 16583/AG/NIA NIH HHS; GM 43825/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ceramides; 0/Tumor Necrosis Factor-alpha; 5072-26-4/Buthionine Sulfoximine; 70-18-8/Glutathione; EC 3.1.1.-/Phospholipases A; EC 3.1.4.12/Sphingomyelin Phosphodiesterase |
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