title: Cadmium induces interleukin-8 production in human peripheral blood mononuclear cells with the concomitant generation of superoxide radicals.
abstract: Acute or chronic exposure to cadmium (Cd) causes severe organ damages with the infiltration of leukocytes, neutrophils in particular occurring in the acute phase. Interleukin-8 (IL-8), a novel neutrophil chemotactic and activating cytokine, is produced by various types of cells in response to a wide variety of inflammatory stimuli. The administration of an antibody against IL-8 has been shown to inhibit neutrophil infiltration in several animal models, indicating a causal relationship between IL-8 and neutrophil infiltration. Hence, in this study we investigated whether Cd induced IL-8 production in human peripheral blood mononuclear cells (PBMC). Cd, over a wide range of concentrations, did induce human PBMC to produce large amounts of bioactive IL-8, the maximal induction being observed at 10(-4) M. The production was inhibited specifically by a metal chelating agent, ethylenediaminetetraacetic acid (EDTA). Steady level of IL-8 mRNA increased within 30 min after the addition of Cd and reached a maximal level at 2 h, decreasing thereafter. A protein synthesis inhibitor, cycloheximide, failed to inhibit IL-8 mRNA accumulation, indicating that new protein synthesis was not required for IL-8 mRNA induction. Concomitantly with the induction of IL-8, within 10 min Cd generated reactive oxygen intermediates (ROI) in human PBMC. A radical scavenger, N-acetyl-L-cysteine (NAC), inhibited both IL-8 production and the generation of ROI, implying the possible involvement of ROI in IL-8 production. This notion was also supported by our findings that a superoxide generating agent, paraquat, induced IL-8 production in human PBMC and that NAC blocked this paraquat-induced IL-8 production.
authors.affiliation: Department of Pharmacology, Kanazawa University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Horiguchi
authors.forename: N
authors.initials: N
authors.lastname: Mukaida
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Teranishi
authors.forename: M
authors.initials: M
authors.lastname: Kasuya
authors.forename: K
authors.initials: K
authors.lastname: Matsushima
mesh_terms: D001483:Base Sequence; D015152:Blotting, Northern; D002104:Cadmium / Q000633:toxicity*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016384:Consensus Sequence; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000097:blood; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D013481:Superoxides / Q000097:blood*; D013997:Time Factors
chemical_list: D016209:Interleukin-8; D012333:RNA, Messenger; D002104:Cadmium; D013481:Superoxides; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase