TY - JOUR
T1 - Gefitinib initiates sterile inflammation by promoting IL-1β and HMGB1 release via two distinct mechanisms
AU - Noguchi, Takuya
AU - Sekiguchi, Yuto
AU - Kudoh, Yuki
AU - Naganuma, Rio
AU - Kagi, Tomohiro
AU - Nishidate, Akiko
AU - Maeda, Kazuhiro
AU - Ishii, Chizuru
AU - Toyama, Takashi
AU - Hirata, Yusuke
AU - Hwang, Gi Wook
AU - Matsuzawa, Atsushi
N1 - Funding Information:
We thank all members of Lab of Health Chemistry for helpful discussions. We would like to thank Editage (www.editage.com) for English language editing. This work was supported by JSPS KAKENHI Grant Numbers JP18H02567, JP18J11303 and JP18K06622, and by MEXT KAKENHI JP17H05518 and JP19H05282. This work was also supported by the Fugaku Trust for Medicinal Research, and the Takeda Science Foundation.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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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U2 - 10.1038/s41419-020-03335-7
DO - 10.1038/s41419-020-03335-7
M3 - Article
C2 - 33414419
AN - SCOPUS:85098880500
SN - 2041-4889
VL - 12
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 1
M1 - 49
ER -
