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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2000-8-22
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pubmed:abstractText |
Chloroquine (CQ) is a lysosomotropic weak base with over 60 years of clinical use for the treatment of malaria and rheumatologic disorders. Consistent with its anti-inflammatory properties, CQ has been shown to interfere with TNF-alpha release from mononuclear phagocytes. Because it is unclear how CQ mediates these immunomodulatory effects, we set out to elucidate its mechanism of action. CQ exhibited dose-dependent inhibition of LPS-induced TNF-alpha release from human PBMC at therapeutically attainable concentrations. Additional studies to determine the specificity of this effect showed that although CQ reduced IL-1beta and IL-6 release, secretion of RANTES was unaffected. CQ acted by reducing TNF-alpha mRNA accumulation without destabilizing its mRNA or interfering with NF-kappaB nuclear translocation or p50/p65 isoform composition of DNA-binding complexes. Intracellular cytokine staining indicated that CQ reduced TNF-alpha production pretranslationally without interfering with TNF-alpha processing or release. We utilized bafilomycin A1 pretreatment to block the pH-dependent trapping of CQ in endosomes and lysosomes. Although bafilomycin A1 alone did not interfere with TNF-alpha expression, preincubation augmented the ability of CQ to reduce TNF-alpha mRNA levels, suggesting that CQ did not act by a lysosomotropic mechanism. Using confocal microscopy, we showed that bafilomycin A1 pretreatment resulted in a dramatic redistribution of quinacrine, a fluorescent congener of CQ, from cytoplasmic vacuoles to the nucleus. These data indicate that CQ inhibits TNF-alpha gene expression without altering translocation of NF-kappaB p50/p65 heterodimers. This dose-dependent effect occurs over a pharmacologically relevant concentration range and does not require pH-dependent lysosomotropic accumulation of CQ.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Bacterial Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Chemokine CCL5,
http://linkedlifedata.com/resource/pubmed/chemical/Chloroquine,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-6,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Macrolides,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B,
http://linkedlifedata.com/resource/pubmed/chemical/NF-kappa B p50 Subunit,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor RelA,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/bafilomycin A
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-1767
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
165
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1534-40
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:10903761-Anti-Bacterial Agents,
pubmed-meshheading:10903761-Biological Transport,
pubmed-meshheading:10903761-Cell Nucleus,
pubmed-meshheading:10903761-Chemokine CCL5,
pubmed-meshheading:10903761-Chloroquine,
pubmed-meshheading:10903761-DNA-Binding Proteins,
pubmed-meshheading:10903761-Dose-Response Relationship, Drug,
pubmed-meshheading:10903761-Dose-Response Relationship, Immunologic,
pubmed-meshheading:10903761-Gene Expression Regulation,
pubmed-meshheading:10903761-Humans,
pubmed-meshheading:10903761-Hydrogen-Ion Concentration,
pubmed-meshheading:10903761-Immunosuppressive Agents,
pubmed-meshheading:10903761-Interleukin-1,
pubmed-meshheading:10903761-Interleukin-6,
pubmed-meshheading:10903761-Leukocytes, Mononuclear,
pubmed-meshheading:10903761-Lipopolysaccharides,
pubmed-meshheading:10903761-Lysosomes,
pubmed-meshheading:10903761-Macrolides,
pubmed-meshheading:10903761-NF-kappa B,
pubmed-meshheading:10903761-NF-kappa B p50 Subunit,
pubmed-meshheading:10903761-Protein Biosynthesis,
pubmed-meshheading:10903761-Protein Processing, Post-Translational,
pubmed-meshheading:10903761-RNA, Messenger,
pubmed-meshheading:10903761-Transcription, Genetic,
pubmed-meshheading:10903761-Transcription Factor RelA,
pubmed-meshheading:10903761-Tumor Necrosis Factor-alpha
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pubmed:year |
2000
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pubmed:articleTitle |
Chloroquine interferes with lipopolysaccharide-induced TNF-alpha gene expression by a nonlysosomotropic mechanism.
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pubmed:affiliation |
Department of Microbiology, Evans Memorial Department of Clinical Research, and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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