title: Sensitization of IFN-gamma Jak-STAT signaling during macrophage 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.
authors.affiliation: Graduate Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Hu
authors.forename: Carmen
authors.initials: C
authors.lastname: Herrero
authors.forename: Wai-Ping
authors.initials: WP
authors.lastname: Li
authors.forename: Taras T
authors.initials: TT
authors.lastname: Antoniv
authors.forename: Erik
authors.initials: E
authors.lastname: Falck-Pedersen
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
authors.forename: James M
authors.initials: JM
authors.lastname: Woods
authors.forename: G Kenneth
authors.initials: GK
authors.lastname: Haines
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008262:Macrophage Activation / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2