title: Tumor necrosis factor receptor 1 associates with CD137 ligand and mediates its reverse signaling.
abstract: Reverse signaling through CD137 ligand (CD137L) potently activates monocytes. However, the underlying mechanism is not well elucidated. This study provides evidence that tumor necrosis factor receptor 1 (TNFR1) acts as a coreceptor for CD137L and mediates CD137L signaling. CD137L colocalizes with TNFR1 on the plasma membrane and binds directly to TNFR1 via its extracellular domain. Using the human monocytic THP-1 cell line, we demonstrate that engagement of CD137L by recombinant CD137 protein promotes cell adhesion, apoptosis, expression of CD14, and production of IL-8 and tumor necrosis factor (TNF). Concomitantly, the expression of TNFR1 protein is down-regulated in response to CD137L activation, due to enhanced extracellular release and internalization of TNFR1. Activation of TNFR1 by TNF protein additively augments CD137L-induced IL-8 expression. Conversely, inhibition of TNFR1 activity by a TNFR1-neutralizing antibody inhibits CD137L-mediated cell adhesion, cell death, CD14 expression, and IL-8 production. Taken together, these data show that TNFR1 associates with CD137L and is required for CD137L reverse signaling.
authors.affiliation: Department of Physiology, Duke–National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Mei Chung
authors.initials: MC
authors.lastname: Moh
authors.forename: Paolo Alberto
authors.initials: PA
authors.lastname: Lorenzini
authors.forename: Charles
authors.initials: C
authors.lastname: Gullo
authors.forename: Herbert
authors.initials: H
authors.lastname: Schwarz
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D002448:Cell Adhesion / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha
keywords: THP-1 cells; TNFR1; monocytes