Persistent inhalation of diesel exhaust particles results in damaged lung cells through formation of reactive oxygen species (ROS), but the details of the toxicity mechanism against monocytes are poorly understood. In this study, we used human promyelomonocytic U937 cells as surrogates of monocytes and investigated the toxicity mechanism initiated by exposure to 9,10-phenanthrenequinone (9,10-PQ), a major quinone component in diesel exhaust particles. A 24-h incubation with 9,10-PQ provoked apoptotic cell death, which was due to signaling through the enhanced ROS generation and concomitant caspase activation. Flow cytometric analyses of U937 cells after long-term exposure to 9,10-PQ revealed induction of differentiation that was evidenced by increasing expression of CD11b/CD18, a cell-surface marker for monocytic differentiation into macrophages. The 9,10-PQ-induced differentiation was significantly abolished by ROS inhibitors, suggesting that ROS generation contributes to cell differentiation. The 9,10-PQ treatment increased the expression of aldo-keto reductase (AKR) 1C3, which reached a peak at 1 to 2 d post-treatment and then declined. The bell-shaped curve of the AKR1C3 expression by 9,10-PQ resembled that caused by phorbol 12-myristate 13-acetate, a differentiation inducer. Additionally, the concomitant treatment with tolfenamic acid, a selective AKR1C3 inhibitor, sensitized the differentiation induced by 9,10-PQ. These results suggest that ROS formation during 9,10-PQ treatment acutely leads to apoptosis of U937 cells and the initiation of monocytic differentiation, which proceeds after the provisional overexpression of AKR1C3.Key words 9,10-phenanthrenequinone; differentiation; aldo-keto reductase 1C3; U937; oxidative stress Diesel exhaust particles (DEP) are believed to be harmful air pollutants that cause significant impediments to respiratory function leading to asthma and carcinogenesis.1,2) The mechanisms underlying their disorders is very complicated due to the involvement of a variety of lung cells such as epithelial cells, macrophages and lymphocytes.2) In the acute phase, macrophages are directly activated in response to stimulation with DEP resulting in the regulation of the immune signaling networks through secretion of pro-inflammatory mediators, cytokines 3) and chemokines. 4) In addition, the inhalation of DEP was shown to increase the number of lung macrophages, 5) which may be involved in clearing the particles by phagocytotic ingestion. 6) Thus, macrophages are believed to play pivotal roles in the cytoprotective responses against DEP. On the other hand, several researchers found that the administration of DEP lowers both antimicrobial and mitochondrial functions in alveolar macrophages through generation of reactive oxygen species (ROS) in addition to activating apoptotic signaling. 7,8) DEP are heterogeneous species that consist of a variety of organic and inorganic chemicals, such as polycyclic aromatic hydrocarbons, nitroaromatic hydrocarbons, heterocycles, aldehydes and quinones. 9)...