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Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation.

TitleSensitization of IFN-gamma Jak-STAT signaling during macrophage activation.
Publication TypeJournal Article
Year of Publication2002
AuthorsHu X, Herrero C, Li W-P, Antoniv TT, Falck-Pedersen E, Koch AE, Woods JM, G Haines K, Ivashkiv LB
JournalNat Immunol
Volume3
Issue9
Pagination859-66
Date Published2002 Sep
ISSN1529-2908
KeywordsAnimals, Carrier Proteins, Cells, Cultured, DNA-Binding Proteins, Gene Expression Regulation, Humans, Interferon-gamma, Intracellular Signaling Peptides and Proteins, Janus Kinase 1, Janus Kinase 2, Macrophage Activation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Repressor Proteins, Signal Transduction, STAT1 Transcription Factor, Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transcriptional Activation
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.

DOI10.1038/ni828
Alternate JournalNat Immunol
PubMed ID12172544
Grant ListAI40987 / AI / NIAID NIH HHS / United States
AI46712 / AI / NIAID NIH HHS / United States
AR46713 / AR / NIAMS NIH HHS / United States
HL58695 / HL / NHLBI NIH HHS / United States

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