title: Stimulation of endothelial IL-8 (eIL-8) production and apoptosis by phenolic metabolites of benzene in HL-60 cells and human bone marrow endothelial cells.
abstract: Benzene toxicity is considered to be elicited by its metabolites and phenolic metabolites of benzene are known to induce apoptosis in leukemia cells in culture and in human bone marrow progenitor cells. One potential mechanism of apoptosis induced by benzene metabolites that has not been examined is the production of pro-apoptotic cytokines such as endothelial IL-8 from endothelial cells in bone marrow stroma. In this study, we utilized HL-60 cells which are known to produce the endothelial form of IL-8 (eIL-8) and human bone marrow endothelial cells (HBMEC) as model systems. Hydroquinone (HQ), Catechol (Cat) and benzenetriol (BT) all induced eIL-8 production and apoptosis in HL-60 cells. HQ induced a marked 50-70 fold stimulation of eIL-8 levels and HL-60 cells were shown to have the eIL-8 receptor, CXCR1 thus enabling an autocrine pathway of apoptosis. However, treatment with recombinant eIL-8 failed to induce apoptosis in HL-60 cells as previously reported and antibodies to either IL-8 or CXCR1 did not significantly abrogate benzene metabolite-induced apoptosis. HQ and Cat but not BT also induced stimulation of eIL-8 production in HBMEC. These data demonstrate that although metabolites of benzene induce marked stimulation of eIL-8, this is unlikely to be responsible for apoptosis induced in HL-60 cells. Our data also demonstrates that phenolic metabolites of benzene stimulate the production of eIL-8 from HBMEC suggesting that higher levels of endothelial-derived cytokines may occur in bone marrow after benzene exposure.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: Daiva
authors.initials: D
authors.lastname: Bironaite
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.forename: Julie L
authors.initials: JL
authors.lastname: Moran
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
authors.forename: David
authors.initials: D
authors.lastname: Ross
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001555:Benzene Derivatives / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018922:HL-60 Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000276:immunology; D009500:Neutralization Tests; D023062:Receptors, Interleukin-8A / Q000276:immunology; D011994:Recombinant Proteins
chemical_list: D000906:Antibodies; D001555:Benzene Derivatives; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D011994:Recombinant Proteins