Particle_Fibre Toxicology 14_51 - SRiedle et al 081217.pdf (936.51 kB)

Pro-inflammatory adjuvant properties of pigment-grade titanium dioxide are augmented by a genotype that potentiates interleukin 1β processing

Download (936.51 kB)
journal contribution
posted on 2023-05-03, 14:50 authored by Sebastian Riedle, Laetitia Pele, Don Otter, Rachel Hewitt, Harjinder Singh, Nicole Roy, Jonathan Powell
Background: Pigment-grade titanium dioxide (TiO2) particles are an additive to some foods (E171 on ingredients lists), toothpastes, and pharma−/nutraceuticals and are absorbed, to some extent, in the human intestinal tract. TiO2 can act as a modest adjuvant in the secretion of the pro-inflammatory cytokine interleukin 1β (IL-1β) when triggered by common intestinal bacterial fragments, such as lipopolysaccharide (LPS) and/or peptidoglycan. Given the variance in human genotypes, which includes variance in genes related to IL-1β secretion, we investigated whether TiO2 particles might, in fact, be more potent pro-inflammatory adjuvants in cells that are genetically susceptible to IL-1β-related inflammation. Methods: We studied bone marrow-derived macrophages from mice with a mutation in the nucleotide-binding oligomerisation domain-containing 2 gene (Nod2m/m), which exhibit heightened secretion of IL-1β in response to the peptidoglycan fragment muramyl dipeptide (MDP). To ensure relevance to human exposure, TiO2 was food-grade anatase (119 ± 45 nm mean diameter ± standard deviation). We used a short ‘pulse and chase’ format: pulsing with LPS and chasing with TiO2 +/− MDP or peptidoglycan. Results: IL-1β secretion was not stimulated in LPS-pulsed bone marrow-derived macrophages, or by chasing with MDP, and only very modestly so by chasing with peptidoglycan. In all cases, however, IL-1β secretion was augmented by chasing with TiO2 in a dose-dependent fashion (5–100 μg/mL). When co-administered with MDP or peptidoglycan, IL-1β secretion was further enhanced for the Nod2m/m genotype. Tumour necrosis factor α was triggered by LPS priming, and more so for the Nod2m/m genotype. This was enhanced by chasing with TiO2, MDP, or peptidoglycan, but there was no additive effect between the bacterial fragments and TiO2. Conclusion: Here, the doses of TiO2 that augmented bacterial fragment-induced IL-1β secretion were relatively high. In vivo, however, selected intestinal cells appear to be loaded with TiO2, so such high concentrations may be ‘exposure-relevant’ for localised regions of the intestine where both TiO2 and bacterial fragment uptake occurs. Moreover, this effect is enhanced in cells from Nod2m/m mice indicating that genotype can dictate inflammatory signalling in response to (nano)particle exposure. In vivo studies are now merited.


Rights statement

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.


  • English

Does this contain Māori information or data?

  • No


Springer Nature

Journal title

Particle and Fibre Toxicology




Riedle, S., Pele, L. C., Otter, D. E., Hewitt, R. E., Singh, H., Roy, N. C., & Powell, J. J. (2017). Pro-inflammatory adjuvant properties of pigment-grade titanium dioxide are augmented by a genotype that potentiates interleukin 1β processing. Particle and Fibre Toxicology, 14, 51. doi:10.1186/s12989-017-0232-2


Riddet Institute

Contract number


Job code


Report number

FBP 78219

Usage metrics


    Ref. manager