title: TNF-αAutocrine Feedback Loops in Human Monocytes: The Pro- and Anti-Inflammatory Roles of the TNF-αReceptors Support the Concept of Selective TNFR1 BlockadeIn Vivo.
abstract: Selective TNFR1 blockade in inflammatory diseases is emerging as a clinical strategy. We studied the roles of the two TNF-αreceptors, TNFR1 and TNFR2, in human monocytes, the principal producer of TNF-αand central to many TNF-αdriven diseases. We hypothesised that TNF-αhas pro- and anti-inflammatory effects on monocytes, occurring differentially via TNFR1 and TNFR2. Monocytes were isolated from healthy human subjects and exposed to LPS, plus/minus the addition of blocking antibodies to TNF-αor its receptors. Pro- and anti-inflammatory cytokine production was quantified using real-time PCR and ELISAs. Cell surface expression of TNFR1/2 was measured by flow cytometry. We demonstrated that monocytes vary in the expression patterns of TNFR1 and TNFR2. Autocrine binding of TNF-αled to sustained upregulation of proinflammatory cytokines via TNFR1. In contrast, autocrine binding via TNFR2 upregulated theanti-inflammatory cytokine, IL-10, without proinflammatory effect. TNFR2 was responsible for binding soluble TNF-αsecreted by monocytes, clearing the cytokine from the pericellular environment. TNFR1 blockade did not change the cell surface expression of TNFR2, leaving this receptor free to upregulate IL-10. These novel results support the concept of selective TNFR1 blockadein vivoin order that positive anti-inflammatory effects of TNF-αcan be retained via TNFR2 ligation.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Jennie M
authors.identifier: 0000-0003-1629-2362
authors.initials: JM
authors.lastname: Gane
authors.affiliation: Lung Investigation Unit, University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Stockley
authors.affiliation: Department of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, UK.
authors.forename: Elizabeth
authors.identifier: 0000-0003-3454-5482
authors.initials: E
authors.lastname: Sapey
mesh_terms: D000328:Adult; D019898:Autocrine Communication; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha