title: Targeting Toll-like receptor 4 prevents cobalt-mediated inflammation.
abstract: Cobalt-chrome alloy is a widely used biomaterial in joint replacements, dental implants and spinal rods. Although it is an effective and biocompatible material, adverse reactions to metal debris (ARMD) have arisen in a minority of patients, particularly in those with metal-on-metal bearing hip replacements. There is currently no treatment for ARMD and once progressive, early revision surgery of the implant is necessary. Therapeutic agents to prevent, halt or reverse ARMD would therefore be advantageous. Cobalt ions activate Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to bacterial lipopolysaccharide (LPS) resulting in the production of pro-inflammatory cytokines and chemokines. We hypothesised that anti-TLR4 neutralising antibodies, reported to inhibit TLR4-mediated inflammation, could prevent the inflammatory response to cobalt ions in an in vitro macrophage cell culture model. This study shows that a monoclonal anti-TLR4 antibody inhibited cobalt-mediated increases in pro-inflammatory IL8, CCL20 and IL1A expression, as well as IL-8 secretion. In contrast, a polyclonal antibody did not prevent the effect of cobalt ions on either IL-8 or IL1A expression, although it did have a small effect on the CCL20 response. Interestingly, both antibodies inhibited cobalt-mediated neutrophil migration although the greater effect was observed with the monoclonal antibody. In summary our data shows that a monoclonal anti-TLR4 antibody can inhibit cobalt-mediated inflammatory responses while a polyclonal antibody only inhibits the effect of specific cytokines. Anti-TLR4 antibodies have therapeutic potential in ARMD although careful antibody design is required to ensure that the LPS response is preserved.
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Helen
authors: H
authors: Lawrence
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Amy Elizabeth
authors: AE
authors: Mawdesley
authors: Musculoskeletal Services, Freeman Hospital, Newcastle upon Tyne, UK.
authors: James Patrick
authors: JP
authors: Holland
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: John Andrew
authors: JA
authors: Kirby
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|Musculoskeletal Services, Freeman Hospital, Newcastle upon Tyne, UK.
authors: David John
authors: DJ
authors: Deehan
authors: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors: Alison Jane
authors: AJ
authors: Tyson-Capper
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003035:Cobalt / Q000009:adverse effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D014131:Trace Elements / Q000009:adverse effects; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014131:Trace Elements; D003035:Cobalt
keywords: Immune response; Immunity; Immunology and Microbiology Section; TLR4; antibody; cobalt; inflammation; metal-on-metal