Comparison of Cellular Uptake and Inflammatory Response via Toll-Like Receptor 4 to Lipopolysaccharide and Titanium Dioxide Nanoparticles

Abstract

The innate immune response is the earliest cellular response to infectious agents and mediates the interactions between microbes and cells. Toll-like receptors (TLRs) play an important role in these interactions. We have already shown that TLRs are involved with the uptake of titanium dioxide nanoparticles (TiO2 NPs) and promote inflammatory responses. In this paper, we compared role of cellular uptake and inflammatory response via TLR 4 to lipopolysaccharide (LPS) and TiO2 NPs. In the case of LPS, LPS binds to LPS binding protein (LBP) and CD 14, and then this complex binds to TLR 4. In the case of TiO2 NPs, the necessity of LBP and CD 14 to induce the inflammatory response and for uptake by cells was investigated using over-expression, antibody blocking, and siRNA knockdown experiments. Our results suggested that for cellular uptake of TiO2 NPs, TLR 4 did not form a complex with LBP and CD 14. In the TiO2 NP-mediated inflammatory response, TLR 4 acted as the signaling receptor without protein complex of LPS, LBP and CD 14. The results suggested that character of TiO2 NPs might be similar to the complex of LPS, LBP and CD 14. These results are important for development of safer nanomaterials.

Release of titanium ions from an implant surface and their effect on cytokine production related to alveolar bone resorption

“…These findings suggest that Ti ions modulate the in vitro and in vivo responses of gingival epithelial cells, even at concentrations previously reported to be noncytotoxic (Makihira et al, 2010). On the other hand, it was recently reported that Ti dioxide nanoparticles can directly bind to TLR-4 without the LPS protein complex, LPS binding protein (LBP) and CD14, increasing the inflammatory response (Chen et al, 2011;Mano et al, 2013). This suggests that Ti dioxide nanoparticles might be similar to this complex (Mano et al, 2013) because binding of the complex of LPS and LBP to CD14 was required for TLR-4 to recognize LPS (Wright et al, 1990).…”

“…On the other hand, it was recently reported that Ti dioxide nanoparticles can directly bind to TLR-4 without the LPS protein complex, LPS binding protein (LBP) and CD14, increasing the inflammatory response (Chen et al, 2011;Mano et al, 2013). This suggests that Ti dioxide nanoparticles might be similar to this complex (Mano et al, 2013) because binding of the complex of LPS and LBP to CD14 was required for TLR-4 to recognize LPS (Wright et al, 1990). Therefore, the mechanism of cellular recognition of Ti materials may be inextricably linked to the presence of TLR-4.…”

Exposure of the murine RAW 264.7 macrophage cell line to dicalcium silicate coating: assessment of cytotoxicity and pro-inflammatory effects

“…TLR4 is involved in the uptake of particles, such as titanium dioxide nanoparticles (TiO 2 NPs), to promote inflammatory responses [48]. Furthermore, wear-debris particles from implants use TLR4 signaling to stimulate macrophages [49].…”

Carbon nanotubes stimulate synovial inflammation by inducing systemic pro-inflammatory cytokines

“…83,85 We therefore studied the activation of NF-κB signaling by determining the changes of IκBα and p65 concentrations. A reduction of IκBα concentration was observed in MWCNT-treated cells, in a dose-dependent manner, from 10 to 20 and 40 µg mL −1 , relative to untreated cells (Fig.…”