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2016 ; 7
(47
): 76471-76478
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Effect of cobalt-mediated Toll-like receptor 4 activation on inflammatory
responses in endothelial cells
#MMPMID27835611
Anjum SA
; Lawrence H
; Holland JP
; Kirby JA
; Deehan DJ
; Tyson-Capper AJ
Oncotarget
2016[Nov]; 7
(47
): 76471-76478
PMID27835611
show ga
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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