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

This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/E534    most recent 00462.2004v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Nareika, A. Articles by Huang, Y. Search for Related Content PubMed PubMed Citation Articles by Nareika, A. Articles by Huang, Y.

Sodium lactate increases LPS-stimulated MMP and cytokine expression in U937 histiocytes by enhancing AP-1 and NF-B transcriptional activities

¹Ralph H. Johnson Veterans Affairs Medical Center; ²Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, and ³Department of Biostatistics, Bioinformatics and Epidemiology, ⁴College of Dental Medicine, Medical University of South Carolina, Charleston, South Carolina

Submitted 30 September 2004 ; accepted in final form 24 May 2005

The plasma lactate concentration in patients with obesity and type 2 diabetes is often higher than that in nondiabetic individuals. Although it is known that increased lactate concentration is an independent risk factor for developing type 2 diabetes, the underlying mechanisms are not well understood. Because inflammation plays an important role in the development of type 2 diabetes, we postulated that increased lactate level might contribute to the pathogenesis of type 2 diabetes by enhancing inflammation. In the present study, we demonstrated that preexposure of U937 macrophage-like cells to sodium lactate increased LPS-stimulated matrix metalloproteinase (MMP)-1, IL-1, and IL-6 secretion. Augmentation of LPS-stimulated MMP-1 secretion was diminished when sodium lactate was replaced by lactic acid that reduced pH in the culture medium. Furthermore, quantitative real-time PCR indicated that the increased secretion of MMP-1, IL-1, and IL-6 was due to increased mRNA expression. To explore the underlying signaling mechanism, blocking studies using specific inhibitors for NF-B and MAPK cascades were performed. Results showed that blocking of either NF-B or MAPK pathways led to the inhibition of MMP-1, IL-1, and IL-6 expression stimulated by sodium lactate, LPS, or both. Finally, electrophoretic mobility shift assays showed a synergy between sodium lactate and LPS on AP-1 and NF-B transcriptional activities. In conclusion, this study has demonstrated for the first time that sodium lactate and LPS exert synergistic effect on MMP and cytokine expression through NF-B and MAPK pathways and revealed a novel mechanism potentially involved in the development of type 2 diabetes and its complications.

diabetes mellitus; lactate; lipopolysaccharide; matrix metalloproteinases; nuclear factor-B; activating protein-1; cytokines

This article has been cited by other articles:

				A. Nareika, Y.-B. Im, B. A Game, E. H Slate, J. J Sanders, S. D London, M. F Lopes-Virella, and Y. Huang High glucose enhances lipopolysaccharide-stimulated CD14 expression in U937 mononuclear cells by increasing nuclear factor {kappa}B and AP-1 activities J. Endocrinol., January 1, 2008; 196(1): 45 - 55. [Abstract] [Full Text] [PDF]

				P. S. Noakes, J. Hale, R. Thomas, C. Lane, S. G. Devadason, and S. L. Prescott Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses Eur. Respir. J., October 1, 2006; 28(4): 721 - 729. [Abstract] [Full Text] [PDF]