Abstract
The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-kappaB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Atherosclerosis / genetics
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Atherosclerosis / immunology
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Carrageenan / immunology
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Case-Control Studies
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Cell Cycle Proteins / metabolism
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Cell Differentiation
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Cell Line
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Gene Expression
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Histone Acetyltransferases / metabolism
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Humans
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In Vitro Techniques
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Inflammation / prevention & control
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Inflammation Mediators / metabolism*
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Kruppel-Like Transcription Factors / antagonists & inhibitors
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / immunology*
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Kruppel-Like Transcription Factors / metabolism
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Macrophage Activation
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Male
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Mice
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Mice, SCID
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Monocytes / cytology
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Monocytes / immunology*
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Monocytes / metabolism
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Phagocytosis
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Promoter Regions, Genetic
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RNA, Small Interfering / genetics
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transcription Factors / metabolism
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p300-CBP Transcription Factors
Substances
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Cell Cycle Proteins
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Inflammation Mediators
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KLF2 protein, human
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Kruppel-Like Transcription Factors
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NF-kappa B
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RNA, Small Interfering
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Transcription Factor AP-1
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Transcription Factors
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Carrageenan
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor