HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 30, 31930-31936, July 23, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/30/31930    most recent M400753200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Srinivasan, S. Articles by Hedrick, C. C. Search for Related Content PubMed PubMed Citation Articles by Srinivasan, S. Articles by Hedrick, C. C. Social Bookmarking                      What's this?

Glucose Regulates Interleukin-8 Production in Aortic Endothelial Cells through Activation of the p38 Mitogen-activated Protein Kinase Pathway in Diabetes^*

Suseela Srinivasan, David T. Bolick, Melissa E. Hatley, Rama Natarajan, Kelly B. Reilly, Michael Yeh¶, Carol Chrestensen||, Thomas W. Sturgill||, and Catherine C. Hedrick||**

From the Department of Diabetes, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, the ^¶Division of Cardiology, UCLA, Los Angeles, California, and the Division of Endocrinology and Metabolism, Cardiovascular Research Center and ^||Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908

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 µM 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.

Received for publication, January 23, 2004 , and in revised form, May 11, 2004.

^* This work was supported by National Institutes of Health Grant P01 HL55798-09 (to C. C. H. and R. N.), the Parke-Davis/Pfizer Atorvastatin Research Award (to C. C. H.), and the American Heart Association (Mid-Atlantic Affiliate) (to C. C. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Cardiovascular Research Center, University of Virginia, P.O. Box 801394, 415 Lane Rd., MR5 Rm. G123, Charlottesville, VA 22908. E-mail: cch6n{at}virginia.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. M. Whetzel, D. T. Bolick, and C. C. Hedrick Sphingosine-1-phosphate inhibits high glucose-mediated ERK1/2 action in endothelium through induction of MAP kinase phosphatase-3 Am J Physiol Cell Physiol, February 1, 2009; 296(2): C339 - C345. [Abstract] [Full Text] [PDF]

				J. A. Ehses, A. Perren, E. Eppler, P. Ribaux, J. A. Pospisilik, R. Maor-Cahn, X. Gueripel, H. Ellingsgaard, M. K.J. Schneider, G. Biollaz, et al. Increased Number of Islet-Associated Macrophages in Type 2 Diabetes Diabetes, September 1, 2007; 56(9): 2356 - 2370. [Abstract] [Full Text] [PDF]

				W. Qi, X. Chen, R. E. Gilbert, Y. Zhang, M. Waltham, M. Schache, D. J. Kelly, and C. A. Pollock High Glucose-Induced Thioredoxin-Interacting Protein in Renal Proximal Tubule Cells Is Independent of Transforming Growth Factor-{beta}1 Am. J. Pathol., September 1, 2007; 171(3): 744 - 754. [Abstract] [Full Text] [PDF]

				M. R. Dasu, S. Devaraj, and I. Jialal High glucose induces IL-1beta expression in human monocytes: mechanistic insights Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E337 - E346. [Abstract] [Full Text] [PDF]

				J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]

				J. W. A. Smit and J. A. Romijn Acute insulin resistance in myocardial ischemia: causes and consequences. Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2006; 10(3): 215 - 219. [Abstract] [PDF]

				L. Qiao, O. A. MacDougald, and J. Shao CCAAT/Enhancer-binding Protein {alpha} Mediates Induction of Hepatic Phosphoenolpyruvate Carboxykinase by p38 Mitogen-activated Protein Kinase J. Biol. Chem., August 25, 2006; 281(34): 24390 - 24397. [Abstract] [Full Text] [PDF]

				S. Devaraj, N. Glaser, S. Griffen, J. Wang-Polagruto, E. Miguelino, and I. Jialal Increased Monocytic Activity and Biomarkers of Inflammation in Patients With Type 1 Diabetes Diabetes, March 1, 2006; 55(3): 774 - 779. [Abstract] [Full Text] [PDF]

				H. Berrahmoune, J. V. Lamont, B. Herbeth, P. S. FitzGerald, and S. Visvikis-Siest Biological Determinants of and Reference Values for Plasma Interleukin-8, Monocyte Chemoattractant Protein-1, Epidermal Growth Factor, and Vascular Endothelial Growth Factor: Results from the STANISLAS Cohort Clin. Chem., March 1, 2006; 52(3): 504 - 510. [Abstract] [Full Text] [PDF]

				D. T. Bolick, S. Srinivasan, K. W. Kim, M. E. Hatley, J. J. Clemens, A. Whetzel, N. Ferger, T. L. Macdonald, M. D. Davis, P. S. Tsao, et al. Sphingosine-1-Phosphate Prevents Tumor Necrosis Factor-{alpha}-Mediated Monocyte Adhesion to Aortic Endothelium in Mice Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 976 - 981. [Abstract] [Full Text] [PDF]

				P. Secchiero, F. Corallini, M. G. di Iasio, A. Gonelli, E. Barbarotto, and G. Zauli TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release Blood, May 1, 2005; 105(9): 3413 - 3419. [Abstract] [Full Text] [PDF]

				F. H. Seeger, J. Haendeler, D. H. Walter, U. Rochwalsky, J. Reinhold, C. Urbich, L. Rossig, A. Corbaz, Y. Chvatchko, A. M. Zeiher, et al. p38 Mitogen-Activated Protein Kinase Downregulates Endothelial Progenitor Cells Circulation, March 8, 2005; 111(9): 1184 - 1191. [Abstract] [Full Text] [PDF]