Research Papers: Immunology:

Effect of cobalt-mediated Toll-like receptor 4 activation on inflammatory responses in endothelial cells

Sami A. Anjum, Helen Lawrence, James P. Holland, John A. Kirby, David J. Deehan and Alison J. Tyson-Capper _

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Oncotarget. 2016; 7:76471-76478. https://doi.org/10.18632/oncotarget.13260

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Sami A. Anjum1,*, Helen Lawrence1,3,*, James P. Holland2,3, John A. Kirby1, David J. Deehan2,3 and Alison J. Tyson-Capper1

1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

2 Department of Orthopaedics, Freeman Hospital, Newcastle upon Tyne, UK

3 Northern Retrieval Centre, Freeman Hospital, Newcastle upon Tyne, UK

* Joint first authors

Correspondence to:

Alison J. Tyson-Capper, email:

Keywords: cobalt, TLR4, endothelium, inflammation, metal-on-metal, Immunology and Microbiology Section, Immune response, Immunity

Received: July 15, 2016 Accepted: November 02, 2016 Published: November 09, 2016


Cobalt-containing metal-on-metal hip replacements are associated with adverse reactions to metal debris (ARMD), including inflammatory pseudotumours, osteolysis, and aseptic implant loosening. The exact cellular and molecular mechanisms leading to these responses are unknown. Cobaltions (Co2+) activate human Toll-like receptor 4 (TLR4), an innate immune receptor responsible for inflammatory responses to Gram negative bacterial lipopolysaccharide (LPS).

We investigated the effect of Co2+-mediated TLR4 activation on human microvascular endothelial cells (HMEC-1), focusing on the secretion of key inflammatory cytokines and expression of adhesion molecules. We also studied the role of TLR4 in Co2+-mediated adhesion molecule expression in MonoMac 6 macrophages.

We show that Co2+ increases secretion of inflammatory cytokines, including IL-6 and IL-8, in HMEC-1. The effects are TLR4-dependent as they can be prevented with a small molecule TLR4 antagonist. Increased TLR4-dependent expression of intercellular adhesion molecule 1 (ICAM1) was also observed in endothelial cells and macrophages. Furthermore, we demonstrate for the first time that Co2+ activation of TLR4 upregulates secretion of a soluble adhesion molecule, sICAM-1, in both endothelial cells and macrophages. Although sICAM-1 can be generated through activity of matrix metalloproteinase-9 (MMP-9), we did not find any changes in MMP9 expression following Co2+ stimulation.

In summary we show that Co2+ can induce endothelial inflammation via activation of TLR4. We also identify a role for TLR4 in Co2+-mediated changes in adhesion molecule expression. Finally, sICAM-1 is a novel target for further investigation in ARMD studies.

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