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.

Objective-It has been shown that plasma level of C-reactive protein (CRP) is an independent predictor for acute coronary syndromes and is associated with plaque weakening. However, the underlying mechanisms are not well understood. In this study, we investigated the effect of CRP on the expression of matrix metalloproteinase-1 (MMP-1) that has been implicated in plaque vulnerability by human U937 histiocytes and monocyte-derived macrophages. Methods and Results-Enzyme-linked immunosorbent assay of MMP-1 in conditioned medium showed that treatment of U937 cells with 100 g/mL of CRP for 24 hour led to a 3-to 5-fold increase in MMP-1 secretion. CRP also markedly stimulated MMP-1 release from human monocyte-derived macrophages. In contrast, CRP had no effect on tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion. Northern blot showed that CRP upregulated MMP-1 mRNA expression. Collagenase activity assay showed that CRP increased collagen-degrading activity in cell-conditioned medium. Furthermore, results showed that the stimulation of MMP-1 secretion by CRP was inhibited by anti-CD32, but not by anti-CD64 antibody, and by mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor PD98059. Finally, Western blot showed that CRP stimulated phosphorylation of extracellular signal-regulated kinase. Key Words: C-reactive protein Ⅲ matrix metalloproteinase Ⅲ arteriosclerosis Ⅲ gene expression C -reactive protein (CRP) is one of acute phase proteins that react to inflammation rapidly. 1 CRP is mainly produced by hepatocytes and its expression is upregulated by inflammatory cytokines such as interleukin-6. 1 Previous studies have well documented that CRP plays a role in host defense against bacterial pathogens and clearance of apoptotic and necrotic cells. 2 However, recent studies have provided evidence that CRP also has undesirable effects, such as promotion of inflammatory process and inflammationassociated atherosclerosis. For example, several investigations have shown that CRP induces the expression of adhesion molecules and chemokines in human endothelial cells [3][4][5] and stimulates release of tissue factor from monocytes. 6 The pathological studies also revealed that CRP is present in atherosclerotic lesions but not in the normal vessel wall. 5,[7][8][9] Furthermore, more than two dozen clinical studies published in the past decade have demonstrated a correlation between plasma CRP levels and acute coronary syndromes. 10 -13 All these studies suggest that CRP may be involved in the progression of atherosclerosis. Conclusions-ThisPlaque rupture and erosion are believed to be the key events that trigger the formation of thrombus and subsequent acute coronary syndromes. 14,15 Because a large number of studies have shown the correlation between plasma CRP levels and acute coronary syndromes, 10 -13 the possible role of CRP in plaque vulnerability has been investigated. A recent histopathological study showed that serum CRP level in patients who died of severe coronary artery disease w...

Modified lipoproteins are immunogenic and play a key pathogenic role in vascular disease. Antibodies to oxidized LDL (oxLDL) are mostly of the proinflammatory IgG 1 and IgG 3 isotypes. We measured IgG and IgM oxLDL antibodies in immune complexes (IC) isolated from 36 patients with type 1 diabetes using a nested case-control design. IgG antibodies predominated over IgM antibodies by an 8:1 ratio. IgG antibody concentrations were higher in the nephropathy cases compared to controls (p=0.09), but no significant difference was observed because of two patients included in the study who had end-stage renal disease (creatinine > 5mg/dl and glomerular filtration rate (GFR) less than 17 ml/min). After eliminating these patients from the analysis, significant positive associations of IgG antibody concentration with serum creatinine and albumin excretion rate were observed after eliminating two patients with significant renal impairment (serum creatinine > 5 mg/dl). Similarly, a negative correlation with estimated glomerular filtration rate was observed in this subsample of 34 patients. Differences in IgM antibody concentrations by nephropathy classification were not supported by the data. In conclusion, the predominance of pro-inflammatory IgG oxLDL antibodies is associated with existence of diabetic nephropathy, and a protective role of IgM antibodies could not be demonstrated.