Linked Life Data

15145956

Source:http://linkedlifedata.com/resource/pubmed/id/15145956

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
30
pubmed:dateCreated
2004-7-19
pubmed:abstractText
We have shown that chronic elevated glucose (25 mm) increases monocyte adhesion to human aortic endothelial cells (EC). This increased adhesion is mediated primarily through induction of interleukin (IL)-8 via activation of the transcription factor AP-1 (Srinivasan, S., Yeh, M., Danziger, E. C., Hatley, M. E., Riggan, A. E., Leitinger, N., Berliner, J. A., and Hedrick, C. C. (2003) Circ. Res. 92, 371-377). In the current study, we identified the elements in the AP-1 transcriptional complex that are activated by glucose. These elements include c-Jun, c-Fos, and Fra-1. AP-1 is activated by cellular oxidative stress, and we have reported significant production of ROS by high glucose-cultured cells. We examined signaling pathways upstream of AP-1 in EC that lead to AP-1 activation by HG. EC cultured in 25 mm glucose had a 2-fold increase in p38 phosphorylation compared with control normal glucose-cultured EC. Inhibition of the p38 pathway using 5 microm SB203580 significantly reduced glucose-mediated IL-8 mRNA production by 60%. Furthermore, blocking p38 pathway activation using a dominant-negative p38 construct significantly reduced glucose-mediated monocyte adhesion by 50%. Thus, glucose-stimulated monocyte adhesion is primarily regulated through phosphorylation of p38 with subsequent activation of AP-1, leading to IL-8 production. To study this pathway in the setting of diabetes, we used the db/db mouse. P38 phosphorylation was increased in diabetic db/db mice compared with control mice. We found a dramatic elevation in plasma levels of KC, the mouse ortholog of IL-8 in diabetic db/db mice (1800 +/- 100 pg/ml KC in db/db versus 300 +/- 75 pg/ml in C57BL/6J control mice, p < 0.0001). Inhibition of the p38 pathway in diabetic db/db mice significantly reduced monocyte adhesion by 50%. Taken together, these data indicate that chronic elevated glucose in diabetes activates the p38 MAP kinase pathway to increase inflammatory IL-8 gene induction and monocyte/endothelial adhesion.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
279
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
31930-6
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:15145956-Animals, pubmed-meshheading:15145956-Base Sequence, pubmed-meshheading:15145956-Cell Adhesion, pubmed-meshheading:15145956-Cells, Cultured, pubmed-meshheading:15145956-DNA Primers, pubmed-meshheading:15145956-Diabetes Mellitus, Type 2, pubmed-meshheading:15145956-Endothelium, Vascular, pubmed-meshheading:15145956-Glucose, pubmed-meshheading:15145956-Humans, pubmed-meshheading:15145956-Interleukin-8, pubmed-meshheading:15145956-MAP Kinase Signaling System, pubmed-meshheading:15145956-Male, pubmed-meshheading:15145956-Mice, pubmed-meshheading:15145956-Mice, Inbred C57BL, pubmed-meshheading:15145956-Mice, Mutant Strains, pubmed-meshheading:15145956-Mitogen-Activated Protein Kinases, pubmed-meshheading:15145956-Models, Biological, pubmed-meshheading:15145956-Monocytes, pubmed-meshheading:15145956-RNA, Messenger, pubmed-meshheading:15145956-p38 Mitogen-Activated Protein Kinases
pubmed:year
2004
pubmed:articleTitle
Glucose regulates interleukin-8 production in aortic endothelial cells through activation of the p38 mitogen-activated protein kinase pathway in diabetes.
pubmed:affiliation
Department of Diabetes, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't