Abstract
Macrophages participate pivotally in the pathogenesis of many chronic inflammatory diseases including atherosclerosis. Adiponectin, a vasculoprotective molecule with insulin-sensitizing and anti-atherogenic properties, suppresses pro-inflammatory gene expression in macrophages by mechanisms that remain incompletely understood. This study investigated the effects of adiponectin on major pro-inflammatory signaling pathways in human macrophages. We demonstrate that pretreatment of these cells with adiponectin inhibits phosphorylation of nuclear factor kappaB inhibitor (IkappaB), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK), induced by either lipopolysaccharide (LPS) or tumor necrosis factor (TNF) alpha, as well as STAT3 phosphorylation induced by interleukin-6 (IL6). Antagonism of IL10 by either neutralizing antibodies or siRNA-mediated silencing did not abrogate the anti-inflammatory actions of adiponectin, indicating that the ability of adiponectin to render human macrophages tolerant to various pro-inflammatory stimuli does not require this cytokine. A systematic search for adiponectin-inducible genes with established anti-inflammatory properties revealed that adiponectin augmented the expression of A20, suppressor of cytokine signaling (SOCS) 3, B-cell CLL/lymphoma (BCL) 3, TNF receptor-associated factor (TRAF) 1, and TNFAIP3-interacting protein (TNIP) 3. These results suggest that adiponectin triggers a multifaceted response in human macrophages by inducing the expression of various anti-inflammatory proteins that act at different levels in concert to suppress macrophage 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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Adiponectin / metabolism
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Adiponectin / pharmacology
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B-Cell Lymphoma 3 Protein
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Cell Line
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DNA-Binding Proteins
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Gene Expression Regulation / drug effects
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Humans
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I-kappa B Proteins / metabolism
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Inflammation / metabolism
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Interleukin-10 / metabolism
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Interleukin-10 / pharmacology*
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Interleukin-6 / metabolism
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Interleukin-6 / pharmacology
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Intracellular Signaling Peptides and Proteins
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipopolysaccharides / pharmacology
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MAP Kinase Signaling System / drug effects*
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Macrophages / metabolism*
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Nuclear Proteins / biosynthesis
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Phosphorylation / drug effects
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Proteins / metabolism
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Proto-Oncogene Proteins / biosynthesis
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STAT3 Transcription Factor / biosynthesis
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TNF Receptor-Associated Factor 1 / biosynthesis
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Transcription Factors / biosynthesis
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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ADIPOQ protein, human
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Adiponectin
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B-Cell Lymphoma 3 Protein
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BCL3 protein, human
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DNA-Binding Proteins
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I-kappa B Proteins
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IL10 protein, human
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IL6 protein, human
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Lipopolysaccharides
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Nuclear Proteins
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Proteins
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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TNF Receptor-Associated Factor 1
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TNIP3 protein, human
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Interleukin-10
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3