title: Opposing regulation of the late phase TNF response by mTORC1-IL-10 signaling and hypoxia in human macrophages.
abstract: Tumor necrosis factor (TNF) is best known for inducing a rapid but transient NF-κB-mediated inflammatory response. We investigated later phases of TNF signaling, after the initial transient induction of inflammatory genes has subsided, in primary human macrophages. TNF signaling induced expression of late response genes, including inhibitors of NF-κB and TLR signaling, with delayed and sustained kinetics 6-24 hr after TNF stimulation. A subset of late phase genes was expressed in rheumatoid arthritis synovial macrophages, confirming their expression under chronic inflammatory conditions in vivo. Expression of a subset of late phase genes was mediated by autocrine IL-10, which activated STAT3 with delayed kinetics. Hypoxia, which occurs at sites of infection or inflammation where TNF is expressed, suppressed this IL-10-STAT3 autocrine loop and expression of late phase genes. TNF-induced expression of IL-10 and downstream genes was also dependent on signaling by mTORC1, which senses the metabolic state of cells and is modulated by hypoxia. These results reveal an mTORC1-dependent IL-10-mediated late phase response to TNF by primary human macrophages, and identify suppression of IL-10 responses as a new mechanism by which hypoxia can promote inflammation. Thus, hypoxic and metabolic pathways may modulate TNF responses during chronic inflammation.
authors: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10021, USA.|Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.
authors: Linda
authors: L
authors: Huynh
authors: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10021, USA.|Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.
authors: Anthony
authors: A
authors: Kusnadi
authors: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.
authors: Sung Ho
authors: SH
authors: Park
authors: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.
authors: Koichi
authors: K
authors: Murata
authors: Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.
authors: Kyung-Hyun
authors: KH
authors: Park-Min
authors: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, 1300 York Avenue, New York, NY 10021, USA.|Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, 535 East 70th Street, New York, NY, 10021, USA.
authors: Lionel B
authors: LB
authors: Ivashkiv
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D051152:Clusterin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D051152:Clusterin; D016753:Interleukin-10; D037102:Lectins; D000076222:Mechanistic Target of Rapamycin Complex 1; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C490989:ARNT2 protein, human; C495242:CLU protein, human; C426228:SIGLEC10 protein, human; C494086:STAT3 protein, human