High Mobility Group box-1 Protects Against Aflatoxin G ₁-induced Pulmonary Epithelial Cell Damage in the Lung Inflammatory Environment

Aflatoxin G₁ (AFG₁) is a member of the carcinogenic aflatoxin family. Our previous studies indicated that oral administration of AFG₁ caused tumor necrosis factor (TNF)-α-dependent inflammation that enhanced oxidative DNA damage in alveolar epithelial cells, which may be related to AFG₁-induced lung carcinogenesis. High mobility group box-1 (HMGB1) is a nuclear DNA-binding protein; the intracellular and extracellular roles of HMGB1 have been shown to contribute to DNA repair and sterile inflammation. The role of HMGB1 in DNA damage in an aflatoxin-induced lung inflammatory environment was investigated in this study. Upregulation of HMGB1, TLR2, and RAGE was observed in AFG₁-induced lung inflamed tissues and adenocarcinoma. Blocking AFG₁-induced inflammation by neutralization of TNF-α inhibited the upregulation of HMGB1 in mouse lung tissues, suggesting that AFG₁-induced TNF-α-dependent inflammation regulated HMGB1 expression. In the in vitro human pulmonary epithelial cell line model, Beas-2b, AFG₁ directly enhanced the cytosolic translocation of HMGB1 and its extracellular secretion. The addition of extracellular soluble HMGB1 protected AFG₁-induced DNA damage through the TLR2/NF-κB pathway in Beas-2b cells. In addition, blockade of endogenous HMGB1 by siRNA significantly enhanced AFG₁-induced damage. Thus, our findings showed that both extracellularly-released and nuclear and cytosolic HMGB1 could protect the cell from AFG₁-induced cell damage in a TNF-α-dependent lung inflammatory environment.

Keywords: Aflatoxin; DNA damage; High mobility group box-1; Lung inflammation; TNF-α.