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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
46
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pubmed:dateCreated |
2005-11-15
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pubmed:abstractText |
Activation of macrophages is important in chronic inflammatory disease states such as atherosclerosis. Proinflammatory cytokines such as interferon-gamma (IFN-gamma), lipopolysaccharide (LPS), or tumor necrosis factor-alpha can promote macrophage activation. Conversely, anti-inflammatory factors such as transforming growth factor-beta1 (TGF-beta1) can decrease proinflammatory activation. The molecular mediators regulating the balance of these opposing effectors remain incompletely understood. Herein, we identify Kruppel-like factor 4 (KLF4) as being markedly induced in response to IFN-gamma, LPS, or tumor necrosis factor-alpha and decreased by TGF-beta1 in macrophages. Overexpression of KLF4 in J774a macrophages induced the macrophage activation marker inducible nitric-oxide synthase and inhibited the TGF-beta1 and Smad3 target gene plasminogen activator inhibitor-1 (PAI-1). Conversely, KLF4 knockdown markedly attenuated the ability of IFN-gamma, LPS, or IFN-gamma plus LPS to induce the iNOS promoter, whereas it augmented macrophage responsiveness to TGF-beta1 and Smad3 signaling. The KLF4 induction of the iNOS promoter is mediated by two KLF DNA-binding sites at -95 and -212 bp, and mutation of these sites diminished induction by IFN-gamma and LPS. We further provide evidence that KLF4 interacts with the NF-kappaB family member p65 (RelA) to cooperatively induce the iNOS promoter. In contrast, KLF4 inhibited the TGF-beta1/Smad3 induction of the PAI-1 promoter independent of KLF4 DNA binding through a novel antagonistic competition with Smad3 for the C terminus of the coactivator p300/CBP. These findings support an important role for KLF4 as a regulator of key signaling pathways that control macrophage activation.
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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 |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cytokines,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/GKLF protein,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Kruppel-Like Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Lipopolysaccharides,
http://linkedlifedata.com/resource/pubmed/chemical/Nitric Oxide Synthase Type II,
http://linkedlifedata.com/resource/pubmed/chemical/Nitrites,
http://linkedlifedata.com/resource/pubmed/chemical/Oligonucleotides, Antisense,
http://linkedlifedata.com/resource/pubmed/chemical/Plasminogen Activator Inhibitor 1,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Rela protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Smad3 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Tgfb1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factor RelA,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta,
http://linkedlifedata.com/resource/pubmed/chemical/Transforming Growth Factor beta1,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha,
http://linkedlifedata.com/resource/pubmed/chemical/p300-CBP Transcription Factors
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
18
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pubmed:volume |
280
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
38247-58
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:16169848-Animals,
pubmed-meshheading:16169848-Binding Sites,
pubmed-meshheading:16169848-Blotting, Northern,
pubmed-meshheading:16169848-Blotting, Western,
pubmed-meshheading:16169848-Cell Line,
pubmed-meshheading:16169848-Cytokines,
pubmed-meshheading:16169848-DNA,
pubmed-meshheading:16169848-Down-Regulation,
pubmed-meshheading:16169848-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:16169848-Gene Deletion,
pubmed-meshheading:16169848-Inflammation,
pubmed-meshheading:16169848-Interferon-gamma,
pubmed-meshheading:16169848-Kruppel-Like Transcription Factors,
pubmed-meshheading:16169848-Lipopolysaccharides,
pubmed-meshheading:16169848-Macrophage Activation,
pubmed-meshheading:16169848-Macrophages,
pubmed-meshheading:16169848-Mice,
pubmed-meshheading:16169848-Models, Biological,
pubmed-meshheading:16169848-Monocytes,
pubmed-meshheading:16169848-Mutation,
pubmed-meshheading:16169848-Nitric Oxide Synthase Type II,
pubmed-meshheading:16169848-Nitrites,
pubmed-meshheading:16169848-Oligonucleotides, Antisense,
pubmed-meshheading:16169848-Phosphorylation,
pubmed-meshheading:16169848-Plasminogen Activator Inhibitor 1,
pubmed-meshheading:16169848-Promoter Regions, Genetic,
pubmed-meshheading:16169848-Protein Binding,
pubmed-meshheading:16169848-Protein Structure, Tertiary,
pubmed-meshheading:16169848-RNA, Messenger,
pubmed-meshheading:16169848-Signal Transduction,
pubmed-meshheading:16169848-Smad3 Protein,
pubmed-meshheading:16169848-Transcription, Genetic,
pubmed-meshheading:16169848-Transcription Factor RelA,
pubmed-meshheading:16169848-Transfection,
pubmed-meshheading:16169848-Transforming Growth Factor beta,
pubmed-meshheading:16169848-Transforming Growth Factor beta1,
pubmed-meshheading:16169848-Tumor Necrosis Factor-alpha,
pubmed-meshheading:16169848-p300-CBP Transcription Factors
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pubmed:year |
2005
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pubmed:articleTitle |
Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages.
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pubmed:affiliation |
Program in Cardiovascular Transcriptional Biology, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. mfeinberg@rics.bwh.harvard.edu
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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