title: Toll-like receptor 4 signaling pathway mediates proinflammatory immune response to cobalt-alloy particles.
abstract: Metal orthopedic implant debris-induced osteolysis of hip bone is a major problem in patients with prosthetic-hips. Although macrophages are the principal targets for implant-wear debris, the receptor(s) and mechanisms underlying these responses are not fully elucidated. We examined whether the TLR4 pathway mediates immune response to metal-on-metal (MoM) implant-generated wear particles. Human monocytes (THP-1) were exposed to Co-alloy particles at increasing particle:cell ratio for 24 h. Challenge with particles caused up-regulation of IL-1β, TNF-α and IL-8, and mediated degradation of cytosolic I-κB and nuclear translocation of NF-κB. Blocking antibodies against TLR4 or gene silencing of MyD88 and IRAK-1 prevented particle-induced I-κB/NF-κB activation response and markedly inhibited IL-8 release. Particle-mediated IL-8 response was not observed in TLR4-negative HEK293T cells; whereas transfection-based TLR4-overexpression in HEK293T enabled particle-sensitivity, as observed by I-κB degradation and IL-8 expression in response to particles. Results demonstrate that Co-alloy particles trigger immune response via the TLR4-MyD88-dependent signaling pathway.
authors.affiliation: Division of Biology, Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), Food and Drug Administration (FDA), USA. pushya.potnis@fda.hhs.gov
authors.forename: Pushya A
authors.initials: PA
authors.lastname: Potnis
authors.forename: Debargh K
authors.initials: DK
authors.lastname: Dutta
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wood
mesh_terms: D000497:Alloys / Q000737:chemistry / Q000494:pharmacology; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003035:Cobalt / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010316:Particle Size; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000497:Alloys; D019138:Antibodies, Blocking; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D016209:Interleukin-8; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D003035:Cobalt; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases