Aflatoxin G1 induced TNF-α-dependent lung inflammation to enhance DNA damage in alveolar epithelial cells.

Abstract

Aflatoxin G1 (AFG1 ), a member of the AF family with cytotoxic and carcinogenic properties, could cause DNA damage in alveolar type II (AT-II) cells and induce lung adenocarcinoma. Recently, we found AFG1 could induce chronic lung inflammation associated with oxidative stress in the protumor stage. Chronic inflammation plays a critical role in cigarette smoke or benzo[a]pyrene-induced lung tissues damage. However, it is unclear whether and how AFG1 -induced lung inflammation affects DNA damage in AT-II cells. In this study, we found increased DNA damage and cytochrome P450 (CYP2A13) expression in AFG1 -induced inflamed lung tissues. Furthermore, we treated the mice with a soluble tumor necrosis factor (TNF)-α receptor and AFG1 and found that TNF-α neutralization inhibited the AFG1 -induced chronic lung inflammation in vivo, and then reversed the CYP2A13 expression and DNA damage in AT-II cells. The results suggest that AFG1 induces TNF-α-dependent lung inflammation to regulate 2A13 expression and enhance DNA damage in AT-II cells. Then, we treated the primary mice AT-II cells and human AT-II like cells (A549) with AFG1 and TNF-α and found that TNF-α enhanced the AFG1 -induced DNA damage in mice AT-II cells as well as A549 cells in vitro. In AFG1 -exposed A549 cells, TNF-α-enhanced DNA damage and apoptosis were reversed by CYP2A13 small interfering RNA. Blocking NF-κB pathway inhibited the TNF-α-enhanced CYP2A13 upregulation and DNA damage confirming that the CYP2A13 upregulation by TNF-α plays an essential role in the activation of AFG1 under inflammatory conditions. Taken together, our findings suggest that AFG1 induces TNF-α-dependent lung inflammation, which upregulates CYP2A13 to promote the metabolic activation of AFG1 and enhance oxidative DNA damage in AT-II cells.