Abstract
The alterations in microenvironment upon chronic arsenic exposure may contribute to arsenic-induced lung carcinogenesis. Immune cells, such as macrophages, play an important role in mediating the microenvironment in the lungs. Macrophages carry out their functions after activation. There are two activation status for macrophages: classical (M1) or alternative (M2); the latter is associated with tumorigenesis. Our previous work showed that long-term arsenic exposure induces transformation of lung epithelial cells. However, the crosstalk between epithelial cells and macrophages upon arsenic exposure has not been investigated. In this study, using a co-culture system in which human lung epithelial cells are cultured with macrophages, we determined that long-term arsenic exposure polarizes macrophages towards M2 status through ROS generation. Co-culture with epithelial cells further enhanced the polarization of macrophages as well as transformation of epithelial cells, while blocking macrophage M2 polarization decreased the transformation. In addition, macrophage M2 polarization decreased autophagy activity, which may account for increased cell transformation of epithelial cells with co-culture of macrophages.
Highlights
Arsenic is a naturally existing element present in food, soil and water, and humans are exposed to arsenic through environmental contamination and occupational exposure
To determine the effect of macrophages on arsenic-induced transformation of lung epithelial cells in this current study, we co-cultured B2B cells with macrophages using transwell plates; THP-1-derived macrophages were placed in the upper compartments and B2B cells in lower compartments
The results indicate that co-culture of macrophages significantly enhanced arsenicinduced cell transformation of B2B cells as colony numbers increased from 27.67 ± 5.51/well in control to 45.33 ± 6.51/well with co-culture, P < 0.05 (Figure 1B)
Summary
Arsenic is a naturally existing element present in food, soil and water, and humans are exposed to arsenic through environmental contamination and occupational exposure. In contrast to the short-term, high dose therapeutic use of arsenic, chronic exposure to environmental levels of arsenic promotes skin, bladder, liver and lung cancers. The US Environmental Protection Agency reduced the permissible level of arsenic in drinking water from 50 ppb to 10 ppb in 2001. Inorganic arsenic compounds promote human lung cancer and the primary route of arsenic exposure in humans is through diet and drinking water. Our previous work showed that long-term arsenic exposure induces transformation of lung epithelial cells in vitro, and xenograft tumor formation in nude mice. Our data indicated that oxidative stress was a driving force to promote, and autophagy was a cell self-protective mechanism against, the carcinogenic actions of arsenic [1]. We later determined that arsenic increased the secretion of inflammatory cytokines by the epithelial cells, which in turn may facilitate arsenic-induced transformation of epithelial cells by inhibiting autophagy [2]
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