Abstract
A general paradigm in signal transduction is ligand-induced feedback inhibition and the desensitization of signaling. We found that subthreshold concentrations of interferon-gamma (IFN-gamma), which did not activate macrophages, increased their sensitivity to subsequent IFN-gamma stimulation; this resulted in increased signal transducer and activator of transcription 1 (STAT1) activation and increased IFN-gamma#150;dependent gene activation. Sensitization of IFN-gamma signaling was mediated by the induction of STAT1 expression by low doses of IFN-gamma that did not effectively induce feedback inhibition. IFN-gamma signaling was sensitized in vivo after IFN-gamma injection, and STAT1 expression was increased after injection of lipopolysaccharide and in rheumatoid arthritis synovial cells. These results identify a mechanism that sensitizes macrophages to low concentrations of IFN-gamma and regulates IFN-gamma responses in acute and chronic inflammation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Carrier Proteins / biosynthesis
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Cells, Cultured
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DNA-Binding Proteins / physiology*
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Gene Expression Regulation
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Humans
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Interferon-gamma / physiology*
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 1
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Janus Kinase 2
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Macrophage Activation / physiology*
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Protein-Tyrosine Kinases / physiology*
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Proto-Oncogene Proteins*
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Repressor Proteins*
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STAT1 Transcription Factor
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Signal Transduction*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / physiology*
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Transcriptional Activation
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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SOCS1 protein, human
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STAT1 Transcription Factor
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STAT1 protein, human
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Interferon-gamma
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Protein-Tyrosine Kinases
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JAK1 protein, human
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JAK2 protein, human
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Janus Kinase 1
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Janus Kinase 2