Interaction between arsenic trioxide (ATO) and human neutrophils
François Binet1, Sonia Chiasson, Denis Girard
1Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, INRS-Institut Armand-Frappier, Laval, QC, Canada.
Human & Experimental Toxicology
|May 27, 2010
Summary
Arsenic trioxide (ATO) induces endoplasmic reticulum (ER) stress and apoptosis in neutrophils. ATO also activates nuclear factor κB (NF-κB) and elevates prostaglandin E2 (PGE2) and interleukin-8 (IL-8) production, independent of caspase-4.
Area of Science:
- Immunology
- Cell Biology
- Toxicology
Background:
- Arsenic trioxide (ATO) induces apoptosis in various cells, including neutrophils.
- ATO has been shown to induce endoplasmic reticulum (ER) stress-related neutrophil apoptosis, but the role of caspase-4 remains unclear.
Purpose of the Study:
- To investigate neutrophil activation by ATO.
- To further confirm ATO as an ER stressor.
- To elucidate the mechanisms of ATO-induced neutrophil apoptosis and cytokine production.
Main Methods:
- Human neutrophils isolated from healthy donors were incubated with ATO in vitro.
- Analysis included GADD153 protein expression, nuclear factor κB (NF-κB) DNA binding activity, prostaglandin E2 (PGE2) production, and cytokine profiling via antibody arrays and ELISA.
- Caspase-4 inhibition was used to assess its role in IL-8 production.
Main Results:
- ATO induced GADD153 expression, NF-κB activation, and PGE2 production.
- Antibody arrays revealed increased cytokine production, predominantly interleukin-8 (IL-8).
- ELISA confirmed elevated IL-8 levels, which were not affected by caspase-4 inhibition.
Conclusions:
- ATO is confirmed as an ER stressor that induces neutrophil apoptosis.
- ATO triggers parallel activation of NF-κB, PGE2, and cytokine production (including IL-8), likely involved in other cellular functions.
- IL-8 production is independent of caspase-4, suggesting this pathway mediates other ATO effects in neutrophils.
