| Attenuation of macrophage apoptosis by the cAMP-signaling system. | |
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MedLine Citation:
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PMID: 11108134 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Previous studies revealed that expression and activation of cyclooxygenase-2 (Cox-2) conveyed a protective principle in murine macrophages, thus attenuating pro-apoptotic actions of chemotherapeutic agents or programmed cell death as a result of massive nitric oxide (NO) generation. Expression of Cox-2 was achieved by treatment of cells with lipopolysaccharide/interferon-gamma or nontoxic doses of NO releasing agents. We reasoned E-type prostanoid formation, and in turn an intracellular cAMP increase as the underlying protective mechanism. To prove our hypothesis, we analyzed the effects of lipophilic cAMP-analogs on NO, cisplatin, or etoposide induced apoptosis in RAW 264.7 macrophages. Selected apoptotic parameters comprised DNA fragmentation (diphenylamine assay), annexin V staining of phosphatidylserine, caspase activity (quantitated by the cleavage of a fluorogenic caspase-3-like substrate Ac-DEVD-AMC), and mitochondrial membrane depolarisation (delta psi). Western blots detected accumulation of the tumor suppressor protein p53, relocation of cytochrome c to the cytosol, and expression of the anti-apoptotic protein Bcl-xL. Prestimulation with lipophilic cAMP-analogs attenuated apoptosis with the notion that cell death parameters were basically absent. To verify gene induction by cAMP in association with protection we established activation of cAMP response element binding protein (CREB) by gel-shift analysis and moreover, treated macrophages with oligonucleotides containing a cAMP-responsive element (CRE) in order to scavenge CREB. Decoy oligonucleotides, but not control oligonucleotides, attenuated cAMP-evoked protection and reestablished pro-apoptotic parameters. We conclude that gene induction by cAMP protects macrophages towards apoptosis that occurs as a result of excessive NO formation or addition of chemotherapeutica. Attenuating programmed cell death by the cAMP-signaling system may be found in association with Cox-2 expression and tumor formation. |
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Authors:
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A von Knethen; B Brüne |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular and cellular biochemistry Volume: 212 ISSN: 0300-8177 ISO Abbreviation: Mol. Cell. Biochem. Publication Date: 2000 Sep |
Date Detail:
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Created Date: 2001-03-22 Completed Date: 2001-05-31 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0364456 Medline TA: Mol Cell Biochem Country: NETHERLANDS |
Other Details:
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Languages: eng Pagination: 35-43 Citation Subset: IM |
Affiliation:
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Department of Medicine IV, Faculty of Medicine, University of Erlangen-Nürnberg, Erlangen, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects, physiology* Bucladesine / pharmacology* Caspase 3 Caspases / metabolism Cell Line Cyclic AMP / physiology* Cyclic AMP Response Element-Binding Protein / metabolism Cyclooxygenase 2 DNA Fragmentation Gene Expression Regulation / drug effects, physiology Genes, fos Isoenzymes / metabolism Macrophages / cytology*, drug effects, physiology* Mice Nitric Oxide / pharmacology Nitric Oxide Donors / pharmacology Phosphatidylserines / metabolism Promoter Regions, Genetic Prostaglandin-Endoperoxide Synthases / metabolism Signal Transduction / physiology* Transcriptional Activation Transfection |
| Chemical | |
Reg. No./Substance:
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0/Cyclic AMP Response Element-Binding Protein; 0/Isoenzymes; 0/Nitric Oxide Donors; 0/Phosphatidylserines; 10102-43-9/Nitric Oxide; 362-74-3/Bucladesine; 60-92-4/Cyclic AMP; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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