Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms

Anticancer drug gefitinib causes inflammation-based side effects, such as interstitial pneumonitis. However, its mechanisms remain unknown. Here, we provide evidence that gefitinib elicits pro-inflammatory responses by promoting mature-interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release. Mitochondrial reactive oxygen species (mtROS) driven by gefitinib stimulated the formation of the NLRP3 (NACHT, LRR and PYD-containing protein 3) inflammasome, leading to mature-IL-1β release. Notably, gefitinib also stimulated HMGB1 release, which is, however, not mediated by the NLRP3 inflammasome. On the other hand, gefitinib-driven mtROS promoted the accumulation of γH2AX, a hallmark of DNA damage, leading to the activation of poly (ADP-ribose) polymerase-1 (PARP-1) and subsequent active release of HMGB1. Together our results reveal the potential ability of gefitinib to initiate sterile inflammation via two distinct mechanisms, and identified IL-1β and HMGB1 as key determinants of gefitinib-induced inflammation that may provide insights into gefitinib-induced interstitial pneumonitis.Subject terms: Inflammasome, Inflammatory diseases     

The applicable condition of Magos' method for mercury measurement under coexistence of selenium

Delayed and incomplete release of Hg⁰ was reported in liver, blood, and spleen, but not in kidneys and brain, of mice simultaneously administered HgCl₂ and Na₂SeO₃ for both inorganic and total mercury determination by Magos' method. This problem was overcome by the treatment of the tissue homogenate with an equal volume of 45% NaOH containing 1% cysteine·HCl at 40°C for more than 30 min and the use of the area under the peak of the mercury release curve on calculaton. In the case of administration of methylmercuric chloride instead of mercuric chloride, the influence of coexistent selenium was not observed for mercury determination by Magos' method in mice within 24 h after dosing.