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

Abstract

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.

High glucose and interferon gamma synergistically stimulate MMP-1 expression in U937 macrophages by increasing transcription factor STAT1 activity

“…Our results showed that high glucose augmented IFNγ-stimulated MMP-1 expression compared with normal glucose. Thus, this finding in combination with our previous reports that high glucose augments lipopolysaccharide (LPS)-stimulated MMP-1 expression (12)(13)(14) clearly indicate that chronic exposure to high glucose enhances the responsiveness of macrophages to inflammatory stimuli.…”

“…U937 histiocytes (resident macrophages) (11) were purchased from American Type Culture Collection (Manassas, VA) and have been used in our previous studies to show the augmentation of lipopolysaccharide (LPS)-stimulated MMP and cytokine expression by high glucose (12)(13)(14). The cells were cultured in a 5% CO 2 atmosphere in RPMI 1640 medium (GIBCO, Invitrogen Cop.…”

“…In the studies to determine the effects of the specific inhibitors of signaling pathways (Calbiochem/EMD Biosciences, Inc., San Diego, CA) on the stimulation of MMP-1 gene expression by IFNγ, U937 cells pre-exposed to normal or high glucose were treated with 100 units/ml of IFNγ in the absence or presence of 10 μM of AG490 (JAK-STAT pathway inhibitor) or bay117085 (NFκB pathway inhibitor) for 24 h. The concentrations of the inhibitors have been applied in the previous studies (13,14). After the treatment, MMP-1 in conditioned medium was quantified using ELISA.…”

Aerobically Derived Lactate Stimulates Revascularization and Tissue Repair via Redox Mechanisms

“…Lactate enhances a remarkable set of actions that could be causally linked to its ability to induce the formation of reactive oxygen species. Elevated lactate induces: (i) HIF-1α stabilization, (ii) VEGF and TGFβ (41), (iii) metalloproteinases (25), (iv) endothelial cell mobility (5), (v) vascularization (current data), (vi) increased collagen synthesis, and its post translational modification and deposition (13,41), (vii) cell proliferation (43), (viii) transcription of genes for proteoglycans, CD44, caveolin-1, Hyal-1 and -2 (11), and (ix) an environment suitable for the recruitment of progenitor cells (current data).…”

High glucose enhances lipopolysaccharide-stimulated CD14 expression in U937 mononuclear cells by increasing nuclear factor κB and AP-1 activities

“…In addition to the effect of high glucose on gene expression as described above, our recent studies have demonstrated that chronic pre-exposure of mononuclear cells to high glucose augments lipopolysaccharide (LPS)-stimulated MMP and proinflammatory cytokine expression (Maldonado et al 2004, Nareika et al 2005, 2006. However, the mechanisms involved in the synergistic upregulation of the genes by high glucose and LPS have not been fully understood.…”