NF‑κB inhibitor DHMEQ inhibits titanium dioxide nanoparticle‑induced interleukin‑1β production: Inhibition of the PM2.5‑induced inflammation model

Abstract

PM2.5 is a particle with a diameter <2.5 µm that is often involved in air pollution. Nanoparticles <100 nm are thought to invade the trachea and lungs to cause inflammation, possibly through the activation of macrophages. On the other hand, titanium dioxide (TiO 2) particles can be used in models of nano-micro-sized particles, as one can prepare the particles with such sizes. TiO 2 particles are classified into Rutile, Anatase, and Brookite types by their crystal structure. Among them, Anatase-type TiO 2 particles with a primary diameter of 50 nm (A50) were reported to induce interleukin (IL)-1β production and secretion effectively in phorbol 12-myristate 13-acetate-treated human monocytic leukemia THP-1 cells (THP-1 macrophages). We previously designed and synthesized dehydroxymethyl-epoxyqinomicin (DHMEQ) as an inhibitor of NF-κB. The present study investigated whether the NF-κB inhibitor DHMEQ inhibits TiO 2 nanoparticle-induced IL-1β production in THP-1 macrophages, and determined the mechanism. As a result, DHMEQ inhibited A50-induced IL-1β secretion in ELISA assays at nontoxic concentrations. It decreased the expression of IL-1β mRNA, which was dependent on NF-κB. Although NLR family pyrin domain containing 3 (NLRP3)-inflammasome-caspase-1 activation is required for the maturation of IL-1β, and DHMEQ reduced the NLRP3 mRNA expression and caspase-1 activity; a caspase-1 inhibitor did not influence the A50-induced IL-1β production. Therefore, it is likely that inhibition of pro-IL-1β expression by DHMEQ may be sufficient to inhibit mature IL-1β production. Thus, DHMEQ may be useful for the amelioration of inflammation in the trachea and lungs caused by inhalation of PM2.5.

PM2.5‐induced pulmonary inflammation via activating of the NLRP3/caspase‐1 signaling pathway

“…Mature IL‐1β and IL‐18 are then released to extracellular space 7 . Interestingly, as an effector of the NLRP3 inflammasome, IL‐1β is a pluripotent pro‐inflammatory cytokine involved in the process of PM2.5‐induced respiratory diseases and considered to play a pivotal role in pulmonary inflammation pathogenesis 8 . For example, Xu et al showed that PM2.5 exposure induced IL‐1β signaling activation and resulted in pulmonary inflammation 9 .…”

Decoding inflammation, its causes, genomic responses, and emerging countermeasures

“…The NF‐ĸB inhibitor structurally related to the antibiotic epoxyquinomycin was reported to inhibit the nuclear translocation of NF‐κB RelA (p65) in TNFα‐stimulated cells without information on the nuclear transport of other SRTFs . This inhibitor also reduced the expression of IL‐1β in human THP‐1 cells challenged with titanium dioxide particles and also reduced skin inflammation in a murine model of atopic dermatitis . Ivermectin, a broad‐spectrum antiparasitic compound, was identified as an inhibitor of importin α/β nuclear import involved in the nuclear transport of some viral proteins .…”

“…184 This inhibitor also reduced the expression of IL-1β in human THP-1 cells challenged with titanium dioxide particles and also reduced skin inflammation in a murine model of atopic dermatitis. 185,186 Ivermectin, a broad-spectrum antiparasitic compound, was identified as an inhibitor of importin α/β nuclear import involved in the nuclear transport of some viral proteins. 187 Its selectivity towards individual importins α remains unclear.…”

Metal Oxide Nanoparticles in Therapeutic Regulation of Macrophage Functions

“…Pro-inflammatory stimuli LPS and IFNγ act via TLR4 to trigger STAT1 phosphorylation and up-regulate the expression of STAT1-dependent genes, and its effect is prolonged by MONPs [125,126]. In the THP1 monocytic cell line, an NFκB inhibitor attenuated Il1β production induced by TiO2 NPs [66]. The anti-inflammatory potential of NPs is also controlled via NFκB down-regulation [57].…”