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. Since 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 pre-exposure of U937 macrophage-like cells to sodium lactate increased lipopolysaccharide (LPS)-stimulated matrix metalloproteinase (MMP)-1, interleukin (IL)-1 and IL-6 secretion. The 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 NFB and MAPK cascades were performed. Results showed that blocking of either NFB 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 NFB 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 NFB and MAPK pathways and revealed a novel mechanism potentially involved in the development of type 2 diabetes and its complications.