title: Interaction between arsenic trioxide (ATO) and human neutrophils.
abstract: The cytotoxic effect of arsenic trioxide (ATO) is known to be mediated by its ability to induce cell apoptosis in a variety of cells, including neutrophils. More recently, we demonstrated that ATO induced several parameters involved in endoplasmic reticulum (ER) stress-induced neutrophil apoptosis but that caspase-4 was not involved. The aim of this study was to better understand how neutrophils are activated by ATO and to further demonstrate that ATO is an ER stressor. Human neutrophils were isolated from healthy blood donors and incubated in vitro in the presence or absence of ATO and several parameters were investigated. We found that ATO induced the expression of the proapoptotic GADD153 protein, a key player involved in ER stress-induced apoptosis, activated nuclear nuclear factor κB (NF-κB) DNA binding activities, and increased prostaglandine E2 (PGE2) production. Using an antibody array approach, we found that ATO increased the production of several cytokines, with interleukin 8 (IL-8) being the predominant one. We confirmed that ATO increased the production of IL-8 by enzyme-linked-immunosorbent assay (ELISA). Treatment with a caspase-4 inhibitor did not inhibit IL-8 production. The results of the present study further support the notion that ATO is an ER stressor and that, although its toxic effect is mediated by induction of apoptosis, this chemical also induced, in parallel, NF-κB activation, the production of PGE2 and several cytokines probably involved in other cell functions. Also, we conclude that the production of IL-8 is not induced by a caspase-4-dependent mechanism, suggesting that ATO-induced caspase-4 activation is involved in other as yet unidentified functions in human neutrophils.
authors.affiliation: Laboratoire de recherche en inflammation et physiologie des granulocytes, Université du Québec, INRS-Institut Armand-Frappier, Laval, QC, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Binet
authors.forename: Sonia
authors.initials: S
authors.lastname: Chiasson
authors.forename: Denis
authors.initials: D
authors.lastname: Girard
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016328:NF-kappa B / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D010087:Oxides / Q000633:toxicity*; D040081:Protein Array Analysis; D051742:Transcription Factor CHOP / Q000096:biosynthesis*
chemical_list: D001152:Arsenicals; D016207:Cytokines; C497249:DDIT3 protein, human; D016328:NF-kappa B; D010087:Oxides; D051742:Transcription Factor CHOP; D015232:Dinoprostone; D000077237:Arsenic Trioxide