title: Arsenite activates NFκB through induction of C-reactive protein.
abstract: C-reactive protein (CRP) is an acute phase protein in humans. Elevated levels of CRP are produced in response to inflammatory cytokines and are associated with atherosclerosis, hypertension, cardiovascular disease and insulin resistance. Exposure to inorganic arsenic, a common environmental toxicant, also produces cardiovascular disorders, namely atherosclerosis and is associated with insulin-resistance. Inorganic arsenic has been shown to contribute to cardiac toxicities through production of reactive oxygen species (ROS) that result in the activation of NFκB. In this study we show that exposure of the hepatic cell line, HepG2, to environmentally relevant levels of arsenite (0.13 to 2 μM) results in elevated CRP expression and secretion. ROS analysis of the samples showed that a minimal amount of ROS are produced by HepG2 cells in response to these concentrations of arsenic. In addition, treatment of FvB mice with 100 ppb sodium arsenite in the drinking water for 6 months starting at weaning age resulted in dramatically higher levels of CRP in both the liver and inner medullary region of the kidney. Further, mouse Inner Medullary Collecting Duct cells (mIMCD-4), a mouse kidney cell line, were stimulated with 10 ng/ml CRP which resulted in activation of NFκB. Pretreatment with 10 nM Y27632, a known Rho-kinase inhibitor, prior to CRP exposure attenuated NFκB activation. These data suggest that arsenic causes the expression and secretion of CRP and that CRP activates NFκB through activation of the Rho-kinase pathway, thereby providing a novel pathway by which arsenic can contribute to metabolic syndrome and cardiovascular disease.
authors.affiliation: Department of Pharmacology & Toxicology, The University of Arizona College of Pharmacy, Tucson, AZ 85721, USA.
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Druwe
authors.forename: James J
authors.initials: JJ
authors.lastname: Sollome
authors.forename: Pablo
authors.initials: P
authors.lastname: Sanchez-Soria
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.forename: Todd D
authors.initials: TD
authors.lastname: Camenisch
authors.forename: Richard R
authors.initials: RR
authors.lastname: Vaillancourt
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D018053:Arsenites / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D018053:Arsenites; D015415:Biomarkers; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017382:Reactive Oxygen Species; C108830:Y 27632; D002097:C-Reactive Protein; D007770:L-Lactate Dehydrogenase; D008156:Luciferases; D054460:rho-Associated Kinases; C015001:arsenite