title: Cadmium-induced IL-6 and IL-8 expression and release from astrocytes are mediated by MAPK and NF-κB pathways.
abstract: Chronic exposure to cadmium has been linked to brain cancers, learning disabilities and memory deficits. Previous studies of cadmium toxicity in the central nervous system report cadmium induces oxidative stress in neurons and astrocytes. In the peripheral system, cadmium promotes interleukin-6 (IL-6) and IL-8 production and release. Elevation of IL-6 expression is linked to the pathogenesis of neurodegenerative diseases and astrogliosis. IL-8 plays a role in angiogenesis of gliomas and neurodegenerative diseases. Herein, the effects of non-toxic concentrations of cadmium on the production of IL-6 and IL-8 and the underlying mechanisms were investigated. U-87 MG human astrocytoma cells and primary human astrocytes were exposed to cadmium chloride. At 24h post-exposure to 1 and 10μM, levels of intracellular cadmium in U-87 MG cells were 11.89±3.59 and 53.08±7.59μg/g wet weight, respectively. These concentrations had minimal effects on cell morphology and viability. IL-6 and IL-8 mRNA levels and secretion increased in dose- and time-dependent manners post cadmium exposure. Acute exposure to cadmium increased phosphorylation of ERK1/2, p38 MAPK, and p65 NF-κB. Pretreatment with U0126-an inhibitor of MEK1 and MEK2 kinases-SB203580-a p38 MAPK inhibitor-and SC-514-an IKKβ inhibitor-suppressed cadmium-induced IL-8 expression and release. Upregulation of cadmium-induced IL-6 was inhibited by U0126 and SC-514, but not SB203580. On the other hand, SP600125-a JNK inhibitor-and celecoxib-a selective COX-2 inhibitor-had no effect on production of both cytokines. In conclusion, non-toxic concentrations of cadmium can stimulate IL-6 and IL-8 release through MAPK phosphorylation and NF-κB activation. Suppressing IL-6 and IL-8 production could be novel approaches to prevent cadmium-induced angiogenesis in gliomas and inflammation in the brain.
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Suttinee
authors.initials: S
authors.lastname: Phuagkhaopong
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Dusadee
authors.initials: D
authors.lastname: Ospondpant
authors.affiliation: Faculty of Pharmaceutical Science, Burapha University, Chonburi, Thailand.
authors.forename: Thitima
authors.initials: T
authors.lastname: Kasemsuk
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Nathawut
authors.initials: N
authors.lastname: Sibmooh
authors.affiliation: Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Sunhapas
authors.initials: S
authors.lastname: Soodvilai
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Power
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand. Electronic address: pornpun.viv@mahidol.edu.
authors.forename: Pornpun
authors.initials: P
authors.lastname: Vivithanaporn
mesh_terms: D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002104:Cadmium / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D002104:Cadmium; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Angiogenesis; Cadmium; ERK1/2; Inflammation; NF-κB; p38 MAPK