Titanium Dioxide Nanoparticles Induce Matrix Metalloprotease 1 in Human Pulmonary Fibroblasts Partly via an Interleukin-1β–Dependent Mechanism

Abstract

Exposure to titanium dioxide (TiO2) nanoparticles (NPs) is associated with lung remodeling, but the underlying mechanisms are unknown. Matrix metalloprotease (MMP)-1 is an important actor in matrix homeostasis and could therefore participate in TiO2 NP effects. Our aim was to evaluate the effects of TiO2 NPs on MMP-1 expression and activity in lung pulmonary fibroblasts and to understand the underlying mechanisms and assess the importance of the physicochemical characteristics of the particles in these effects. Human pulmonary fibroblasts (MRC-5 cell line and primary cells) were exposed to 10 or 100 μg/cm(2) TiO2 (two anatases, two anatase/rutile mix, one rutile NP, and one micrometric) and carbon black (CB) NPs for 6 to 48 hours. We examined cell viability, MMP-1 expression and activity, and the implication of oxidative stress, transforming growth factor (TGF)-β, extracellular MMP inducer, and IL-1β in MMP-1 expression. All TiO2 NPs induced MMP-1 (mRNA and protein expression), repression of procollagen-1, and α-actin expression, but only the two anatase/rutile mix induced MMP-1 activity. Micrometric TiO2 had smaller effects than TiO2 NPs, and CB NPs did not induce MMP-1. MMP-1 induction by TiO2 NPs was not related to TGF-β, oxidative stress, or EMPRIN expression but was related to IL-1β expression, which partly drives MMP-1 induction by two TiO2 NPs (one anatase/rutile mix and the rutile one). Taken together, our results show that TiO2 NPs are potent inducers and regulators of MMP-1 expression and activity, partly via an IL-1β-dependent mechanism. This may explain TiO2 lung remodeling effects.

Intracellular Signal Modulation by Nanomaterials

“…Others have also shown that NLRP3 inflammasome activation by TiO 2 involves K + efflux but did not require NP uptake leading to neutrophil recruitment in vivo through IL-1 alpha secretion (Yazdi et al, 2010). The activation of the inflammasome could not only lead to inflammation but also to cell death through pyroptosis as observed for CB NPs (Reisetter et al, 2011) or induction of matrix metalloprotease 1 as shown for TiO 2 NPs in pulmonary fibroblasts (Armand et al, 2013). Recent studies have shown that in synergy with toll-like receptor ligands, certain CB NPs could promote the activation of the NLRP3 inflammasome.…”

Silicon‐based quantum dots induce inflammation in human lung cells and disrupt extracellular matrix homeostasis

“…Standards of MMP-9 (92 kDa) and MMP-2 (72 kDa) (Chemicon) were used to identify gelatinases. The enzymatic activity detected by casein zymography corresponding to MMP-1 was established based on its molecular mass of 54 kDa, being intensely expressed in pulmonary fibroblasts and MRC-5 cells [70,71].…”

Potential Antifibrotic and Angiostatic Impact of Idebenone, Carnosine and Vitamin E in Nano-Sized Titanium Dioxide-Induced Liver Injury

“…Perturbation of TGF-β1 signaling has been implicated in several developmental disorders and in various human diseases, including cancer, fibrosis and autoimmune diseases [35]. n-TiO 2 was found to be a potent inducer and regulator of matrix metalloproteinase-1 (MMP-1) and TGF-β expression and activity, partly via an IL-1β-dependent mechanism [36]. It has also been reported that the expression of TGF-β in mouse liver accelerates hepatocarcinogenesis and enhances DNA damage due to chronic oxidative stress.…”

“…Interestingly, n-TiO 2 is a potent inducer of transforming growth factor-beta (TGF-β) expression, partly via an interleukin-1 beta (IL-1β)-dependent mechanism [5]. n-TiO 2 also induced higher levels of transcription factors, Smads, and growth factors [6].…”