IL-33 enhances Siglec-8 mediated apoptosis of human eosinophils

Ho Jeong Na, Sherry A. Hudson, Bruce S. Bochner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

IL-33 activates eosinophils directly via the ST2 receptor. Like IL-5, IL-33 induces eosinophilia and eosinophilic airway inflammation in mouse models and primes human eosinophil responses. Previously, we reported that IL-5 priming enhances Siglec-8 mediated mitochondrial and reactive oxygen species (ROS)-dependent eosinophilic apoptosis and eliminates caspase dependence of this cell death process. Whether IL-33, like IL-5, augments pro-apoptotic pathways involving receptors such as Siglec-8 and in a similar manner has not been explored. Annexin-V labeling was performed to detect apoptosis in human eosinophils pre-incubated with or without a range of concentrations of IL-33 and/or IL-5 in the presence or absence of Siglec-8 monoclonal antibody (mAb) 2C4 and inhibitors of caspases. Tetramethyl-rhodamine staining was used as a marker of mitochondrial membrane potential loss and injury. ROS production was determined by measuring the superoxide dismutase-inhibitable reduction of cytochrome c. Cleavage of poly(ADP-ribose) polymerase (PARP) was assessed using Western blotting. Eosinophils cultured alone or with mAb 2C4 underwent low levels of apoptosis at 24. h. 2C4-induced eosinophil apoptosis was markedly and equally enhanced after culture for 24. h with either IL-33 or IL-5, although IL-5 was more potent. Effects on apoptosis with IL-33 and IL-5 were synergistic. In contrast, percentages of cells exhibiting reduced mitochondrial membrane potential were greater with IL-33 than IL-5 and effects of these cytokines were also synergistic. Antimycin, an inhibitor of mitochondrial electron transport, almost completely inhibited 2C4-induced apoptosis with either IL-33 or IL-5. Surprisingly, 2C4-induced eosinophil ROS production was significantly enhanced with IL-5 but not IL-33. Siglec-8-mediated apoptosis in the presence of IL-33 was more sensitive in magnitude than IL-5 to inhibition by the pan-caspase inhibitor Z-VAD-FMK, yet both cytokine conditions were associated with PARP cleavage. These data demonstrate that IL-33 is as effective but less potent than IL-5 in enhancing Siglec-8-mediated eosinophil apoptosis, and can synergize with IL-5. Eosinophils primed by IL-33 and/or IL-5 . in vivo would be expected to display enhanced susceptibility to undergoing Siglec-8-induced apoptosis.

Original languageEnglish (US)
Pages (from-to)169-174
Number of pages6
JournalCytokine
Volume57
Issue number1
DOIs
StatePublished - Jan 2012

Funding

This work was supported in part by grants from the National Institutes of Health ( AI41472 and AI72265 to BSB). Dr. Bochner also received support as a Cosner Scholar in Translational Research from The Johns Hopkins University School of Medicine and is a co-author on existing and pending Siglec-8-related patents. If Siglec-8-related products are developed in the future, Dr. Bochner may be entitled to a share of royalties received by The Johns Hopkins University on the potential sale of such products. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Keywords

  • Apoptosis
  • Eosinophils
  • IL-33
  • Reactive oxygen species
  • Siglec-8

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Biochemistry
  • Immunology and Allergy
  • Immunology

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