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

Autor: Takuya Noguchi, Yuto Sekiguchi, Yuki Kudoh, Rio Naganuma, Tomohiro Kagi, Akiko Nishidate, Kazuhiro Maeda, Chizuru Ishii, Takashi Toyama, Yusuke Hirata, Gi-Wook Hwang, Atsushi Matsuzawa
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Cell Death and Disease, Vol 12, Iss 1, Pp 1-17 (2021)
Druh dokumentu: article
ISSN: 2041-4889
DOI: 10.1038/s41419-020-03335-7
Popis: Abstract 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.
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