Cadmium induces interleukin-8 production in human peripheral blood mononuclear cells with the concomitant generation of superoxide radicals.
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.
Horiguchi
H
H
Department of Pharmacology, Kanazawa University, Japan.
Mukaida
N
N
Okamoto
S
S
Teranishi
H
H
Kasuya
M
M
Matsushima
K
K
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
D016209:Interleukin-8; D012333:RNA, Messenger; D002104:Cadmium; D013481:Superoxides; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase