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Article: Double-stranded RNA - Activated protein kinase mediates induction of interleukin-8 expression by deoxynivalenol, shiga toxin 1, and ricin in monocytes

TitleDouble-stranded RNA - Activated protein kinase mediates induction of interleukin-8 expression by deoxynivalenol, shiga toxin 1, and ricin in monocytes
Authors
KeywordsImmunotoxicity
Kinase
Ribotoxic stress chemokine
Issue Date2008
PublisherOxford University Press. The Journal's web site is located at http://toxsci.oxfordjournals.org/
Citation
Toxicological Sciences, 2008, v. 105 n. 2, p. 322-330 How to Cite?
AbstractTranslational inhibitors such as the trichothecene mycotoxin deoxynivalenol (DON) and ribosomal inhibitory proteins (RIPs) induce mitogen-activated protein kinase (MAPK)-driven chemokine and cytokine production by a mechanism known as the ribotoxic stress response (RSR). Double-stranded RNA-activated protein kinase (PKR) associates with the ribosome making it uniquely positioned to sense 28S ribosomal RNA damage and initiate the RSR. We have previously shown that PKR mediates DON-induced MAPK phosphorylation in macrophages and monocytes. The purpose of this study was to test the hypothesis that PKR is essential for induction of interleukin (IL)-8 expression in monocytes by DON and two prototypical RIPs, ricin, and Shiga toxin 1 (Stx1). Preincubation of human monocytic U937 cells with the PKR inhibitors C16 and 2-aminopurine (2-AP) blocked DON-induced expression of IL-8 protein and mRNA. Induction of IL-8 expression was similarly impaired in U937 cells stably transfected with a dominant negative PKR plasmid (UK9M) as compared with cells transfected with control plasmid (UK9C). Nuclear factor-kappa B binding, which has been previously shown to be a requisite for DON-induced IL-8 transcription, was markedly reduced in UK9M cells as compared with UK9C cells. As observed for DON, ricin-, and Stx1-induced IL-8 expression was suppressed by the PKR inhibitors C16 and 2-AP as well as impaired in UK9M cells. Taken together, these data indicate that PKR plays a common role in IL-8 induction by DON and the two RIPs, suggesting that this kinase might be a critical factor in RSR. © The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/80064
ISSN
2015 Impact Factor: 3.88
2015 SCImago Journal Rankings: 1.686
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Public Health ServiceES03358
DK58833
Funding Information:

Public Health Service Grants (ES03358 and DK58833) to J.J.P.

References

 

DC FieldValueLanguage
dc.contributor.authorGray, JSen_HK
dc.contributor.authorBae, HKen_HK
dc.contributor.authorLi, JCBen_HK
dc.contributor.authorLau, ASen_HK
dc.contributor.authorPestka, JJen_HK
dc.date.accessioned2010-09-06T08:01:57Z-
dc.date.available2010-09-06T08:01:57Z-
dc.date.issued2008en_HK
dc.identifier.citationToxicological Sciences, 2008, v. 105 n. 2, p. 322-330en_HK
dc.identifier.issn1096-6080en_HK
dc.identifier.urihttp://hdl.handle.net/10722/80064-
dc.description.abstractTranslational inhibitors such as the trichothecene mycotoxin deoxynivalenol (DON) and ribosomal inhibitory proteins (RIPs) induce mitogen-activated protein kinase (MAPK)-driven chemokine and cytokine production by a mechanism known as the ribotoxic stress response (RSR). Double-stranded RNA-activated protein kinase (PKR) associates with the ribosome making it uniquely positioned to sense 28S ribosomal RNA damage and initiate the RSR. We have previously shown that PKR mediates DON-induced MAPK phosphorylation in macrophages and monocytes. The purpose of this study was to test the hypothesis that PKR is essential for induction of interleukin (IL)-8 expression in monocytes by DON and two prototypical RIPs, ricin, and Shiga toxin 1 (Stx1). Preincubation of human monocytic U937 cells with the PKR inhibitors C16 and 2-aminopurine (2-AP) blocked DON-induced expression of IL-8 protein and mRNA. Induction of IL-8 expression was similarly impaired in U937 cells stably transfected with a dominant negative PKR plasmid (UK9M) as compared with cells transfected with control plasmid (UK9C). Nuclear factor-kappa B binding, which has been previously shown to be a requisite for DON-induced IL-8 transcription, was markedly reduced in UK9M cells as compared with UK9C cells. As observed for DON, ricin-, and Stx1-induced IL-8 expression was suppressed by the PKR inhibitors C16 and 2-AP as well as impaired in UK9M cells. Taken together, these data indicate that PKR plays a common role in IL-8 induction by DON and the two RIPs, suggesting that this kinase might be a critical factor in RSR. © The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://toxsci.oxfordjournals.org/en_HK
dc.relation.ispartofToxicological Sciencesen_HK
dc.rightsToxicological Sciences. Copyright © Oxford University Press.en_HK
dc.subjectImmunotoxicityen_HK
dc.subjectKinaseen_HK
dc.subjectRibotoxic stress chemokineen_HK
dc.titleDouble-stranded RNA - Activated protein kinase mediates induction of interleukin-8 expression by deoxynivalenol, shiga toxin 1, and ricin in monocytesen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1096-6080&volume=105&issue=2&spage=322&epage=30&date=2008&atitle=Double-stranded+RNA-activated+protein+kinase+mediates+induction+of+interleukin-8+expression+by+deoxynivalenol,+Shiga+toxin+1,+and+ricin+in+monocytesen_HK
dc.identifier.emailLi, JCB: jamesli@hku.hken_HK
dc.identifier.emailLau, AS: asylau@hku.hken_HK
dc.identifier.authorityLi, JCB=rp00496en_HK
dc.identifier.authorityLau, AS=rp00474en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1093/toxsci/kfn128en_HK
dc.identifier.pmid18599499-
dc.identifier.pmcidPMC2721672-
dc.identifier.scopuseid_2-s2.0-52049095281en_HK
dc.identifier.hkuros161110en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-52049095281&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume105en_HK
dc.identifier.issue2en_HK
dc.identifier.spage322en_HK
dc.identifier.epage330en_HK
dc.identifier.isiWOS:000259207400009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridGray, JS=13805652800en_HK
dc.identifier.scopusauthoridBae, HK=24536787500en_HK
dc.identifier.scopusauthoridLi, JCB=23103447500en_HK
dc.identifier.scopusauthoridLau, AS=7202626202en_HK
dc.identifier.scopusauthoridPestka, JJ=7101824985en_HK

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