Arsenite activates NFκB through induction of C-reactive protein
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...
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| Veröffentlicht in: | Toxicology and applied pharmacology 2012-06, Vol.261 (3), p.263-270 |
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| creator | Druwe, Ingrid L. Sollome, James J. Sanchez-Soria, Pablo Hardwick, Rhiannon N. Camenisch, Todd D. Vaillancourt, Richard R. |
| description | 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 2μM) 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 100ppb sodium arsenite in the drinking water for 6months 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 10ng/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.
► Exposure to arsenic can induce the expression and secretion of CRP. ► Mice treated with NaAsO2 showed higher levels of CRP in both the liver and kidney. ► mIMCD-3 were stimulated with CRP which resulted in activation of NFκB. ► CRP activates NFκB through activation of the Rho-kinase pathway. ► Data provide novel pathway for arsenic role in metabolic and cardiovascular disease. |
| doi_str_mv | 10.1016/j.taap.2012.04.005 |
| format | Article |
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► Exposure to arsenic can induce the expression and secretion of CRP. ► Mice treated with NaAsO2 showed higher levels of CRP in both the liver and kidney. ► mIMCD-3 were stimulated with CRP which resulted in activation of NFκB. ► CRP activates NFκB through activation of the Rho-kinase pathway. ► Data provide novel pathway for arsenic role in metabolic and cardiovascular disease.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2012.04.005</identifier><identifier>PMID: 22521605</identifier><identifier>CODEN: TXAPA9</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>60 APPLIED LIFE SCIENCES ; Acute phase substances ; Amides - pharmacology ; Animals ; ARSENIC ; Arsenite ; Arsenites - pharmacology ; ARTERIOSCLEROSIS ; Biological and medical sciences ; Biomarkers - analysis ; Biotransformation - drug effects ; Blotting, Western ; C-reactive protein ; C-Reactive Protein - analysis ; C-Reactive Protein - biosynthesis ; C-Reactive Protein - physiology ; Cardiovascular diseases ; Cell Line ; Chemical and industrial products toxicology. Toxic occupational diseases ; CONCENTRATION RATIO ; CRP ; Cytokines ; DRINKING WATER ; Enzyme-Linked Immunosorbent Assay ; Female ; GLOBULINS ; Heart ; Humans ; HYPERTENSION ; IMMUNITY ; Immunohistochemistry ; INSULIN ; Kidney ; Kidney - drug effects ; Kidney - metabolism ; Kidney - pathology ; KIDNEYS ; L-Lactate Dehydrogenase - metabolism ; LIVER ; Liver - drug effects ; Liver - metabolism ; Liver - pathology ; Luciferases - metabolism ; LYMPHOKINES ; Medical sciences ; Metabolic diseases ; Metabolic disorders ; Metabolic syndrome ; Metals and various inorganic compounds ; MICE ; Miscellaneous ; NF-kappa B - genetics ; NF-kappa B - metabolism ; Other metabolic disorders ; Protein Kinase Inhibitors - pharmacology ; Pyridines - pharmacology ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Rho-associated kinase ; rho-Associated Kinases - antagonists & inhibitors ; SECRETION ; SODIUM ; Sodium arsenite ; Toxicants ; TOXICITY ; Toxicology ; Transfection ; Weaning</subject><ispartof>Toxicology and applied pharmacology, 2012-06, Vol.261 (3), p.263-270</ispartof><rights>2012 Elsevier Inc.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><rights>2012 Elsevier Inc. All rights reserved. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-a28ad62c571376d7aa22ceffc5967dfe094f1c01bc0acd2ac436103cb065ceea3</citedby><cites>FETCH-LOGICAL-c546t-a28ad62c571376d7aa22ceffc5967dfe094f1c01bc0acd2ac436103cb065ceea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.taap.2012.04.005$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26049760$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22521605$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/22215336$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Druwe, Ingrid L.</creatorcontrib><creatorcontrib>Sollome, James J.</creatorcontrib><creatorcontrib>Sanchez-Soria, Pablo</creatorcontrib><creatorcontrib>Hardwick, Rhiannon N.</creatorcontrib><creatorcontrib>Camenisch, Todd D.</creatorcontrib><creatorcontrib>Vaillancourt, Richard R.</creatorcontrib><title>Arsenite activates NFκB through induction of C-reactive protein</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>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 2μM) 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 100ppb sodium arsenite in the drinking water for 6months 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 10ng/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.
► Exposure to arsenic can induce the expression and secretion of CRP. ► Mice treated with NaAsO2 showed higher levels of CRP in both the liver and kidney. ► mIMCD-3 were stimulated with CRP which resulted in activation of NFκB. ► CRP activates NFκB through activation of the Rho-kinase pathway. ► Data provide novel pathway for arsenic role in metabolic and cardiovascular disease.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Acute phase substances</subject><subject>Amides - pharmacology</subject><subject>Animals</subject><subject>ARSENIC</subject><subject>Arsenite</subject><subject>Arsenites - pharmacology</subject><subject>ARTERIOSCLEROSIS</subject><subject>Biological and medical sciences</subject><subject>Biomarkers - analysis</subject><subject>Biotransformation - drug effects</subject><subject>Blotting, Western</subject><subject>C-reactive protein</subject><subject>C-Reactive Protein - analysis</subject><subject>C-Reactive Protein - biosynthesis</subject><subject>C-Reactive Protein - physiology</subject><subject>Cardiovascular diseases</subject><subject>Cell Line</subject><subject>Chemical and industrial products toxicology. Toxic occupational diseases</subject><subject>CONCENTRATION RATIO</subject><subject>CRP</subject><subject>Cytokines</subject><subject>DRINKING WATER</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Female</subject><subject>GLOBULINS</subject><subject>Heart</subject><subject>Humans</subject><subject>HYPERTENSION</subject><subject>IMMUNITY</subject><subject>Immunohistochemistry</subject><subject>INSULIN</subject><subject>Kidney</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>KIDNEYS</subject><subject>L-Lactate Dehydrogenase - metabolism</subject><subject>LIVER</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Luciferases - metabolism</subject><subject>LYMPHOKINES</subject><subject>Medical sciences</subject><subject>Metabolic diseases</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Metals and various inorganic compounds</subject><subject>MICE</subject><subject>Miscellaneous</subject><subject>NF-kappa B - genetics</subject><subject>NF-kappa B - metabolism</subject><subject>Other metabolic disorders</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyridines - pharmacology</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Rho-associated kinase</subject><subject>rho-Associated Kinases - antagonists & inhibitors</subject><subject>SECRETION</subject><subject>SODIUM</subject><subject>Sodium arsenite</subject><subject>Toxicants</subject><subject>TOXICITY</subject><subject>Toxicology</subject><subject>Transfection</subject><subject>Weaning</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcGO0zAQhi0EYkvhBTigSAiJS8LYSZxEQojdigWkFVxA4ma5k8nWVWp3bacSr7YPwTPh0LLAhZMP883v_5-fsaccCg5cvtoWUet9IYCLAqoCoL7HFhw6mUNZlvfZAqDiOUD77Yw9CmELAF1V8YfsTIhacAn1gr0994GsiZRpjOagI4Xs0-WP24ssbrybrjeZsf2URs5mbshWuadfIGV77yIZ-5g9GPQY6MnpXbKvl---rD7kV5_ff1ydX-VYVzLmWrS6lwLrhpeN7ButhUAaBqw72fQDJWcDR-BrBI290FiVkkOJa5A1Eulyyd4cdffTekc9ko1ej2rvzU7778ppo_6dWLNR1-6gyrpr244ngedHAReiUQFTZtygs5YwKiEEr8tSJurl6RvvbiYKUe1MQBpHbclNQXEQ0NbQpAsvmTii6F0InoY7MxzUXJDaqrkgNRekoFKpoLT07O8Ydyu_G0nAixOgA-px8NqiCX84CVXXSEjc6yNH6egHQ36ORBapN35O1DvzPx8_ARsBsAM</recordid><startdate>20120615</startdate><enddate>20120615</enddate><creator>Druwe, Ingrid L.</creator><creator>Sollome, James J.</creator><creator>Sanchez-Soria, Pablo</creator><creator>Hardwick, Rhiannon N.</creator><creator>Camenisch, Todd D.</creator><creator>Vaillancourt, Richard R.</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20120615</creationdate><title>Arsenite activates NFκB through induction of C-reactive protein</title><author>Druwe, Ingrid L. ; Sollome, James J. ; Sanchez-Soria, Pablo ; Hardwick, Rhiannon N. ; Camenisch, Todd D. ; Vaillancourt, Richard R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c546t-a28ad62c571376d7aa22ceffc5967dfe094f1c01bc0acd2ac436103cb065ceea3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Acute phase substances</topic><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>ARSENIC</topic><topic>Arsenite</topic><topic>Arsenites - pharmacology</topic><topic>ARTERIOSCLEROSIS</topic><topic>Biological and medical sciences</topic><topic>Biomarkers - analysis</topic><topic>Biotransformation - drug effects</topic><topic>Blotting, Western</topic><topic>C-reactive protein</topic><topic>C-Reactive Protein - analysis</topic><topic>C-Reactive Protein - biosynthesis</topic><topic>C-Reactive Protein - physiology</topic><topic>Cardiovascular diseases</topic><topic>Cell Line</topic><topic>Chemical and industrial products toxicology. Toxic occupational diseases</topic><topic>CONCENTRATION RATIO</topic><topic>CRP</topic><topic>Cytokines</topic><topic>DRINKING WATER</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Female</topic><topic>GLOBULINS</topic><topic>Heart</topic><topic>Humans</topic><topic>HYPERTENSION</topic><topic>IMMUNITY</topic><topic>Immunohistochemistry</topic><topic>INSULIN</topic><topic>Kidney</topic><topic>Kidney - drug effects</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>KIDNEYS</topic><topic>L-Lactate Dehydrogenase - metabolism</topic><topic>LIVER</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Luciferases - metabolism</topic><topic>LYMPHOKINES</topic><topic>Medical sciences</topic><topic>Metabolic diseases</topic><topic>Metabolic disorders</topic><topic>Metabolic syndrome</topic><topic>Metals and various inorganic compounds</topic><topic>MICE</topic><topic>Miscellaneous</topic><topic>NF-kappa B - genetics</topic><topic>NF-kappa B - metabolism</topic><topic>Other metabolic disorders</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyridines - pharmacology</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Rho-associated kinase</topic><topic>rho-Associated Kinases - antagonists & inhibitors</topic><topic>SECRETION</topic><topic>SODIUM</topic><topic>Sodium arsenite</topic><topic>Toxicants</topic><topic>TOXICITY</topic><topic>Toxicology</topic><topic>Transfection</topic><topic>Weaning</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Druwe, Ingrid L.</creatorcontrib><creatorcontrib>Sollome, James J.</creatorcontrib><creatorcontrib>Sanchez-Soria, Pablo</creatorcontrib><creatorcontrib>Hardwick, Rhiannon N.</creatorcontrib><creatorcontrib>Camenisch, Todd D.</creatorcontrib><creatorcontrib>Vaillancourt, Richard R.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Druwe, Ingrid L.</au><au>Sollome, James J.</au><au>Sanchez-Soria, Pablo</au><au>Hardwick, Rhiannon N.</au><au>Camenisch, Todd D.</au><au>Vaillancourt, Richard R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Arsenite activates NFκB through induction of C-reactive protein</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2012-06-15</date><risdate>2012</risdate><volume>261</volume><issue>3</issue><spage>263</spage><epage>270</epage><pages>263-270</pages><issn>0041-008X</issn><eissn>1096-0333</eissn><coden>TXAPA9</coden><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 2μM) 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 100ppb sodium arsenite in the drinking water for 6months 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 10ng/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.
► Exposure to arsenic can induce the expression and secretion of CRP. ► Mice treated with NaAsO2 showed higher levels of CRP in both the liver and kidney. ► mIMCD-3 were stimulated with CRP which resulted in activation of NFκB. ► CRP activates NFκB through activation of the Rho-kinase pathway. ► Data provide novel pathway for arsenic role in metabolic and cardiovascular disease.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>22521605</pmid><doi>10.1016/j.taap.2012.04.005</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 60 APPLIED LIFE SCIENCES Acute phase substances Amides - pharmacology Animals ARSENIC Arsenite Arsenites - pharmacology ARTERIOSCLEROSIS Biological and medical sciences Biomarkers - analysis Biotransformation - drug effects Blotting, Western C-reactive protein C-Reactive Protein - analysis C-Reactive Protein - biosynthesis C-Reactive Protein - physiology Cardiovascular diseases Cell Line Chemical and industrial products toxicology. Toxic occupational diseases CONCENTRATION RATIO CRP Cytokines DRINKING WATER Enzyme-Linked Immunosorbent Assay Female GLOBULINS Heart Humans HYPERTENSION IMMUNITY Immunohistochemistry INSULIN Kidney Kidney - drug effects Kidney - metabolism Kidney - pathology KIDNEYS L-Lactate Dehydrogenase - metabolism LIVER Liver - drug effects Liver - metabolism Liver - pathology Luciferases - metabolism LYMPHOKINES Medical sciences Metabolic diseases Metabolic disorders Metabolic syndrome Metals and various inorganic compounds MICE Miscellaneous NF-kappa B - genetics NF-kappa B - metabolism Other metabolic disorders Protein Kinase Inhibitors - pharmacology Pyridines - pharmacology Reactive oxygen species Reactive Oxygen Species - metabolism Rho-associated kinase rho-Associated Kinases - antagonists & inhibitors SECRETION SODIUM Sodium arsenite Toxicants TOXICITY Toxicology Transfection Weaning |
| title | Arsenite activates NFκB through induction of C-reactive protein |
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