Attenuation of the macrophage inflammatory activity by TiO2 nanotubes via inhibition of MAPK and NF-κB pathways

Abstract

Biomaterial implantation in a living tissue triggers the activation of macrophages in inflammatory events, promoting the transcription of pro-inflammatory mediator genes. The initiation of macrophage inflammatory processes is mainly regulated by signaling proteins of mitogen-activated protein kinase (MAPK) and by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We have previously shown that titania nanotubes modified Ti surfaces (Ti/TiO 2 ) mitigate the immune response, compared with flat Ti surfaces; however, little is known regarding the underlying mechanism. Therefore, the aim of this study is to investigate the mechanism(s) by which this nanotopography attenuates the inflammatory activity of macrophages. Thus, we analyzed the effects of TiO 2 nanotubes on the activation of MAPK and NF-κB signaling pathways in standard and lipopolysaccharide-evoked conditions. Results showed that the Ti/TiO 2 significantly reduce the expression levels of the phosphorylated forms of p38, ERK1/2, c-Jun NH 2 -terminal kinase (JNK), IKKβ, and IkB-α. Furthermore, a significant reduction in the p65 nuclear accumulation on the nanotubular surface was remarked. Following, by using specific MAPK inhibitors, we observed that lipopolysaccharide-induced production of monocyte chemotactic protein-1 and nitric oxide was significantly inhibited on the Ti/TiO 2 surface via p38 and ERK1/2, but not via JNK. However, the selective inhibitor for JNK signaling pathway (SP600125) was effective in reducing tumor necrosis factor alpha release as well as monocyte chemotactic protein-1 and nitric oxide production. Altogether, these data suggest that titania nanotubes can attenuate the macrophage inflammatory response via suppression of MAPK and NF-κB pathways providing a potential mechanism for their anti-inflammatory activity.

<p>TiO₂ Nanotubes Alleviate Diabetes-Induced Osteogenetic Inhibition</p>

“…9 Yu et al demonstrated that, compared with the small-diameter TNT specimen, the cellular behavior of large-diameter TNT specimens was better under high oxidative stress. 40,41 Similarly, in this study, under high-glucose conditions, the TNT surface with a diameter of approximately 80 nm provided good biocompatibility and osteogenetic ability compared with the SLA surface.…”

Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression

“…As is well known, in addition to RAGE, AGEs can bind with several other receptors such as AGE-receptor complex, scavenger receptor, and Toll-like receptor 4 (TLR-4) to transmit messages [ 24 , 25 ]. Furthermore, besides NF κ B pathway, MAPK and STAT signaling have been proven to be implicated in driving inflammatory response in macrophages [ 26 , 27 ]. Therefore, RAGE/NF κ B signaling is just one of the many pathways mediating the inflammatory response induced by AGEs; other potential pathways remain to be studied.…”

Anti-Inflammatory Activity of Populus deltoides Leaf Extract via Modulating NF-κB and p38/JNK Pathways

“…MAPK rapidly responds to a variety of extracellular stimuli and regulates essential cellular events to control a vast array of physiological processes, including macrophage-mediated inflammatory responses [13,14]. The MAPK signaling pathway, involving extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38, is activated by sequential phosphorylation events, and mediates signaling cascades leading to the activation of various transcription factors, such as NF-κB [15,16].…”