Linked Life Data

17615156

Source:http://linkedlifedata.com/resource/pubmed/id/17615156

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2007-9-12
pubmed:abstractText
Numerous studies have demonstrated a central role of renal tubular epithelial cells in the etiology of kidney injury and disease through the elaboration of inflammatory mediators. However, little is known about the cellular signaling mechanisms involved in this process. In this study we employed normal rat kidney epithelial (NRK52E) cells to identify a novel LPS-induced signaling pathway in which RhoA-mediated AP-1 activity promotes expression of cyclooxygenase-2 (COX-2) with consequent feedback inhibition of NF-kappaB activation through IKKbeta. Inhibition of RhoA signaling using either the RhoA kinase inhibitor Y-27632 or a dominant negative mutant of RhoA (RhoA-DN) dramatically extended the duration of p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity following LPS treatment. Prolongation of events associated with NF-kappaB activation was also observed in cells pretreated and/or cotransfected with the JNK inhibitor SP600125 or deletion mutants of MEKK1 (MEKK1-KD) or Jun (Jun-DN). Conversely, constitutive expression of RhoA prevented NF-kappaB activation by LPS, and this effect was reversed by cotransfection with MEKK1-KD. In addition, we found that the RhoA/AP-1 signaling axis plays a necessary role in COX-2 expression by LPS and that this effect is independent of NF-kappaB activation. Moreover, inhibition of COX-2 activity results in persistent p65-DNA binding, IkappaBalpha phosphorylation, and IKKbeta activity, similar to that observed after prevention of RhoA/AP-1 axis signaling. These findings suggest that COX-2 links the RhoA/AP-1 signaling cascade to NF-kappaB activation, thereby defining a novel integrated model for regulation of the inflammatory response of kidney epithelial cells to LPS and potentially other external stimuli.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0363-6143
pubmed:author
pubmed:issnType
Print
pubmed:volume
293
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
C1160-70
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:17615156-Animals, pubmed-meshheading:17615156-Cell Line, pubmed-meshheading:17615156-Cyclooxygenase 2, pubmed-meshheading:17615156-Epithelial Cells, pubmed-meshheading:17615156-Feedback, Physiological, pubmed-meshheading:17615156-I-kappa B Kinase, pubmed-meshheading:17615156-JNK Mitogen-Activated Protein Kinases, pubmed-meshheading:17615156-Kidney Tubules, pubmed-meshheading:17615156-Lipopolysaccharides, pubmed-meshheading:17615156-MAP Kinase Kinase Kinase 1, pubmed-meshheading:17615156-Nephritis, pubmed-meshheading:17615156-Rats, pubmed-meshheading:17615156-Signal Transduction, pubmed-meshheading:17615156-Transcription, Genetic, pubmed-meshheading:17615156-Transcription Factor AP-1, pubmed-meshheading:17615156-Transcription Factor RelA, pubmed-meshheading:17615156-rhoA GTP-Binding Protein
pubmed:year
2007
pubmed:articleTitle
RhoA regulation of NF-kappaB activation is mediated by COX-2-dependent feedback inhibition of IKK in kidney epithelial cells.
pubmed:affiliation
Dept. of Environmental and Occupational Health Sciences, Univ. of Washington, 4225 Roosevelt Way NE, Suite 100, Seattle, WA 98105, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural