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

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Riedle, Sebastian 
Pele, Laetitia C 
Otter, Don E 
Singh, Harjinder 


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.



Cells, Cultured, Macrophages, Animals, Mice, Inbred C57BL, Mice, Mutant Strains, Titanium, Acetylmuramyl-Alanyl-Isoglutamine, Lipopolysaccharides, Tumor Necrosis Factor-alpha, Inflammation Mediators, Adjuvants, Immunologic, Food Additives, Dose-Response Relationship, Drug, Genotype, Phenotype, Mutation, Female, Interleukin-1beta, Nod2 Signaling Adaptor Protein

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Particle and fibre toxicology

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BioMed Central
MRC (MR/R005699/1)