title: The immunobiology of cobalt: demonstration of a potential aetiology for inflammatory pseudotumours after metal-on-metal replacement of the hip.
abstract: Abnormal wear of cobalt-containing metal-on-metal joints is associated with inflammatory pseudotumours. Cobalt ions activate human toll-like receptor 4 (TLR4), which normally responds to bacterial lipopolysaccharide (LPS) in sepsis. Activation of TLR4 by LPS increases the expression of chemokines IL-8 and CXCL10, which recruit leukocytes and activated T-cells, respectively. This study was designed to determine whether cobalt induces a similar inflammatory response to LPS by promoting the expression of IL-8 and CXCL10. A human monocytic cell line, derived from acute monocytic leukaemia, was treated with cobalt ions and expression of IL-8 and CXCL10 measured at mRNA and protein levels. Cobalt-treated macrophages showed a 60-fold increase in IL-8 mRNA, and an eightfold increase in production of the mature chemokine (both p < 0.001); expression of the CXCL10 gene and protein was also significantly increased by cobalt (both p < 0.001). Experiments were also performed in the presence of CLI-095, a TLR4-specific antagonist which abrogated the cobalt-mediated increase in IL-8 and CXCL10 expression. These findings suggest that cobalt ions induce inflammation similar to that observed during sepsis by the simultaneous activation of two TLR4-mediated signalling pathways. These pathways result in increased production of IL-8 and CXCL10, and may be implicated in pseudotumour formation following metal-on-metal replacement.
authors.affiliation: Newcastle University, Institute of Cellular Medicine, 3rd Floor, William Leech Building, Faculty of Medical Sciences, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: H
authors.initials: H
authors.lastname: Lawrence
authors.affiliation: Freeman Hospital, Department of Orthopaedics, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: D
authors.initials: D
authors.lastname: Deehan
authors.affiliation: Freeman Hospital, Department of Orthopaedics, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: J
authors.initials: J
authors.lastname: Holland
authors.affiliation: Newcastle University, Institute of Cellular Medicine, 3rd Floor, William Leech Building, Faculty of Medical Sciences, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: J
authors.initials: J
authors.lastname: Kirby
authors.affiliation: Newcastle University, Institute of Cellular Medicine, 3rd Floor, William Leech Building, Faculty of Medical Sciences, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Tyson-Capper
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000378:metabolism; D003035:Cobalt / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006104:Granuloma, Plasma Cell / Q000209:etiology* / Q000276:immunology; D006622:Hip Prosthesis / Q000009:adverse effects*; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007592:Joint Diseases / Q000209:etiology* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D061825:Metal-on-Metal Joint Prostheses / Q000009:adverse effects*; D009000:Monocytes / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D016209:Interleukin-8; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003035:Cobalt
keywords: CXCL10; Cobalt; Hip replacement; IL-8; Metal-on-metal; TLR4