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 six 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 whch 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.

Chemoprevention Against Arsenic-Induced Mutagenic DNA Breakage and Apoptotic Liver Damage in Rat Via Antioxidant and SOD1 Upregulation by Green Tea (Camellia sinensis) which Recovers Broken DNA Resulted from Arsenic-H2O2Related in Vitro Oxidant Stress

“…Evidence suggests both ROS and CRP can activate the important transcription factor NF-κ-β [8] and several mitogen-activated protein kinases (MAPKs) [46]. In the present investigation, results on DNA fragmentation show that Cu, Fe, and As are highly potent to initiate the DNA strand-breaking event in vivo and in vitro model.…”

“…Arsenic and ROS-induced significant elevations of CRP have been noticed in vivo in mouse and in vitro in human hepatocarcinoma HepG2 cell lines [8]. Evidence suggests both ROS and CRP can activate the important transcription factor NF-κ-β [8] and several mitogen-activated protein kinases (MAPKs) [46].…”

“…Arsenic-exposed human elevates tissue necrotic marker lactate dehydrogenase (LDH) [7]. Arsenic-induced and ROS-regulated c-reactive protein (CRP) and transcription factor NF-κ-β activation may overexpress certain gene relating to cellular apoptotic degeneration [8]. Similarly, activation of transcription factor Nrf2 is also reported [9], and its antioxidant response pathway is regarded as the primary cellular defense against the cytotoxic effects of oxidative stress [10].…”

Aqueous Extract of Carica Papaya Linn Roots Halts Sodium Arsenite-Induced Renal Inflammation through Inhibiting Adenosine Deaminase, 8-Hydroxy-2′-Deoxyguanosine, C-Reactive Protein and Inducible Nitric Oxide Synthase Activity

“…Arsenic exposure has been proven to cause inflammation; this may be a mechanism for arsenic-induced diseases, as inflammation is involved in the pathogenesis of many chronic diseases, including cardiovascular disease, metabolic syndrome (36), chronic kidney disease (37), and cancer (38). Chronic exposure of rats to 100 ppm sodium arsenite in drinking water resulted in an increase in the acute-phase protein C-reactive protein (CRP) in the kidney (39).…”

Environmental Endocrine Disruption of Energy Metabolism and Cardiovascular Risk

“…Activation of the aryl hydrocarbon receptor (AhR) induces vascular inflammation and promotes atherosclerosis in apoE−/− mice, and the AhR is also a common target for a number of diverse EDCs including TCDD [94], dioxin-like PCBs [133], and the fungicide cyprodinil [134]. Systemic inflammation has also been shown to be increased in mice exposed to aerosolized particulate matter [110] and arsenite [135], and TCDD exposure was associated with the induction of global inflammatory gene responses [80]. …”