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

• Published in: American journal of physiology: endocrinology and metabolism Vol. 289; no. 4; p. E534
• Main Authors: Nareika, Alena, He, Lin, Game, Bryan A, Slate, Elizabeth H, Sanders, John J, London, Steven D, Lopes-Virella, Maria F, Huang, Yan
• Format: Journal Article
• Language: English
• Published: United States 01-10-2005
• Subjects: Cytokines - metabolism; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation - drug effects; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Lipopolysaccharides - administration & dosage; Matrix Metalloproteinases - metabolism; NF-kappa B - metabolism; Sodium Lactate - administration & dosage; Transcription Factor AP-1 - metabolism; Transcriptional Activation - drug effects; Transcriptional Activation - physiology; U937 Cells
• ISSN: 0193-1849

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-1beta, 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-1beta, and IL-6 was due to increased mRNA expression. To explore the underlying signaling mechanism, blocking studies using specific inhibitors for NF-kappaB and MAPK cascades were performed. Results showed that blocking of either NF-kappaB or MAPK pathways led to the inhibition of MMP-1, IL-1beta, 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-kappaB 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-kappaB and MAPK pathways and revealed a novel mechanism potentially involved in the development of type 2 diabetes and its complications.