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.

抗癌药物吉非替尼会引起基于炎症的副作用，例如间质性肺炎。然而，其机制仍然未知。在这里，我们提供证据表明吉非替尼通过促进成熟白细胞介素 1β (IL-1β) 和高迁移率族框 1 (HMGB1) 的释放来引发促炎反应。吉非替尼驱动的线粒体活性氧 (mtROS) 刺激了 NLRP3（NACHT、LRR 和 PYD 蛋白 3）炎性体的形成，导致成熟的 IL-1β 释放。值得注意的是，吉非替尼也刺激了 HMGB1 的释放，然而，这不是由 NLRP3 炎症小体介导的。另一方面，吉非替尼驱动的 mtROS 促进了 γH2AX 的积累，这是 DNA 损伤的标志，导致聚（ADP-核糖）聚合酶-1（PARP-1）的激活和随后的 HMGB1 的主动释放。