title: Titanium particles induce the immediate early stress responsive chemokines IL-8 and MCP-1 in osteoblasts.
abstract: Exposure of human osteoblasts to ultrafine titanium (Ti) particles has been shown to alter osteoblast gene expression. We previously reported that Ti particles can increase IL-6 release and suppress the gene expression of procollagens alpha1[I] and alpha1[III] in human osteoblasts. In this study, we now demonstrate that Ti particles can rapidly induce the chemotactic cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), two immediate early stress responsive chemokines important for the activation and chemotaxis of neutrophils and macrophages, respectively. In MG-63 osteosarcoma cells and bone marrow derived primary osteoblasts Ti particles selectively increased the steady state levels of IL-8 and MCP-1 mRNA in a time and concentration dependent manner. The increased chemokine mRNA correlated with increased secretion of IL-8 and MCP-1 protein. Actinomycin D, a potent RNA polymerase II inhibitor, blocked the Ti particle induction of IL-8 and MCP-1 mRNA expression, whereas cycloheximide, which inhibits protein synthesis, failed to inhibit chemokine gene expression suggesting Ti particles directly target activation of chemokine gene transcription. Consistent with a transcriptional mechanism not involving new protein synthesis, we demonstrate that Ti particles induce the binding of the p65 and p50 subunits of the latent transcription factor NF-kappaB to the IL-8 gene promoter. Taken together, these data demonstrate that Ti particles can activate transcription of the stress responsive chemokine genes IL-8 and MCP-1 in human osteoblasts.
authors.affiliation: Department of Immunology/Microbiology, Rush-Presbyterian-St. Luke's Medical Center, Rush University, Chicago, IL 60612, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Fritz
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.forename: Csaba
authors.initials: C
authors.lastname: Vermes
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Jacobs
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Roebuck
mesh_terms: D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004247:DNA / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013312:Stress, Physiological / Q000378:metabolism*; D014025:Titanium / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018932:Chemokine CCL2; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D004247:DNA; D014025:Titanium