The Ca2+-dependent pathway contributes to changes in the subcellular localization and extracellular release of interleukin-33

• Published in: Biochemical and biophysical research communications Vol. 530; no. 4; pp. 699 - 705
• Main Authors: Momota, Masatoshi, Nagayama, Mizuka, Okude, Haruna, Ishii, Ken J., Ori, Daisuke, Kawasaki, Takumi, Kawai, Taro
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2020
• Subjects: Ca2+ influx; IL-33; Pyroptosis; IL-33; Ca2+ influx; Pyroptosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.07.127

Interleukin-33 (IL-33) is a member of the IL-1 cytokine family and plays critical roles in facilitating type-2 immune responses. IL-33 is localized in the nucleus and released to the extracellular milieu during cell death, although the precise mechanisms underlying IL-33 mobilization remain unclear. Here, we found that nigericin, a toxin derived from Streptomyces hygroscopicus, promoted IL-33 translocation from the nucleus to the cytosol before extracellular release. This translocation was inhibited by chelating Ca2+ with EGTA or membrane protection by glycine treatment. Ca2+ ionophore A23187 stimulation caused IL-33 translocation to the cytoplasm but was not sufficient for extracellular release. However, IL-33 release was induced by detergent treatment, which indicates that membrane rupture is required for IL-33 release. The pore-forming pyroptosis executor gasdermin D was cleaved following nigericin stimulation, and overexpression of the cleaved gasdermin D-N-terminal fragment that forms the membrane pore sufficiently induced IL-33 release, which was blocked by EGTA and glycine. Together, these findings suggest that Ca2+-dependent signals and gasdermin D pore formation are required for robust IL-33 production. •Nigericin induces IL-33 translocation from the nucleus to the cytoplasm before extracellular release in HEK293T cells.•This translocation was inhibited by chelating Ca2+ with EGTA or membrane protection by glycine treatment.•Overexpression of gasdermin D-N-terminal fragment induced IL-33 release, which was blocked by EGTA and glycine.•These results suggest that Ca2+-dependent signals and GSDMD pore formation are required for robust IL-33 release.