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

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 a 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. © the author(s).