Nrf2 regulates the activation of THP-1 cells induced by chloral hydrate.

ABSTRACT

Trichloroethylene (TCE) triggers a severe hypersensitivity syndrome in the occupational population dependent on dendritic cells (DCs). Chloral hydrate (CH), the major oxidative metabolite of TCE, has been proved to be the culprit causative substance of TCE-induced hypersensitivity by human patch tests. Because redox imbalance is essential for chemical sensitizers-induced maturation of DCs, we predicted that CH would activate DCs by the nuclear factor E2-related factor 2 (Nrf2)-mediated antioxidant response. This study selected THP-1 cells as the in vitro DC model, and we evaluated the cell activation markers, intracellular oxidative stress, and Nrf2 pathway related genes expression in response to CH in THP-1 cells. CH displayed significant stimulation of THP-1 cells activation, including CD54 and CD86 expression, IL-8 release, and cell migration, and damaged the redox balance by triggering ROS generation, GSH consumption, and antioxidase activities modulation. The levels of Nrf2 and its downstream genes (HO-1 and NQO1) in mRNA and protein expressions were upregulated by CH, and CH also promoted the nuclear translocation of Nrf2. Subsequently, we investigated the effects of antioxidant on Nrf2-mediated cell defense in CH treated cells. Pretreatment with curcumin dramatically reduced cell activation and oxidative stress triggered by CH in THP-1 cells. We also confirmed the specific role of Nrf2 in CH-induced cell activation using NRF2-knockout cells. Deficiency of Nrf2 inhibited cell activation and downregulated HO-1 and NQO1 expression in CH-challenged cells. These findings suggest that Nrf2-dependent redox homeostasis plays a pivotal role in CH-induced activation of THP-1 cells, thereby providing new knowledge of the allergen as well as the molecular mechanism involving in TCE-induce hypersensitivity syndrome.