Inflammation Accelerates Copper-Mediated Cytotoxicity Through Induction Of Six-Transmembrane Epithelial Antigens Of Prostate 4 Expression

Copper is an essential trace metal, but imbalance in copper homeostasis can induce oxidative damage. Inflammation is a fundamental element of various pulmonary diseases. Although a positive relationship between copper and chronic pulmonary diseases has been reported, the underlying reasons are still not clear. The copper level in the sputum of patients with various pulmonary diseases was measured. An inflammatory model was established to evaluate the impact of inflammation on copper uptake in the lung. We found that the level of sputum copper was increased in patients with various pulmonary diseases, especially chronic obstructive pulmonary disease and asthma. Then, we confirmed that mice with pulmonary inflammation were susceptible to copper-mediated oxidative damage because of copper overload in lung tissue. Further investigation demonstrated that interleukin (IL)-17 and tumor necrosis factor (TNF)-alpha exerted synergistic effects in airway epithelial cells by upregulating the expression of six-transmembrane epithelial antigens of prostate 4 (STEAP4), a metalloreductase that reduces extracellular copper ions from the cupric state to the cuprous state and facilitates copper uptake. Inhibition of STEAP4 decreased the copper uptake of cells and inhibited copper-mediated oxidative damage. Moreover, we demonstrated that the upregulation of STEAP4 by IL-17 and TNF-alpha was largely dependent on TNF receptor-associated factor 4 (TRAF4). Traf4(-/-) mice were resistant to copper-mediated oxidative damage. Our data suggest a novel IL-17/TNF-alpha-TRAF4-STEAP4 axis that regulates copper homeostasis.