Titanium particles induce the immediate early stress responsive chemokines IL‐8 and MCP‐1 in osteoblasts

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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 α1[I] and α1[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‐κB 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. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.