Poster presentation. Abstract: Matrix metalloproteinases (MMPs) play a crucial role in the destabilization of atherosclerotic plaques that may lead to plaque rupture-triggered acute coronary syndrome. Although it is known that interleukin 6 (IL-6) is associated with atherosclerosis, and diabetes increases acute coronary events, the regulation of MMP expression in mononuclear cells by IL-6 and the impact of high glucose on the regulation have not been well documented. In the present study, we found that IL-6 stimulated MMP-1 expression in a concentration- and time-dependent manner in U937 mononuclear cells and high glucose further increased IL-6-stimulated MMP-1 expression by 2-fold. By comparing the stimulatory effect of IL-6 with that of lipopolysaccharide (LPS) on MMP-1 expression, we found that IL-6 was 3-fold more effective than LPS at 1 and 10 ng/ml, suggesting that IL-6 is a potent stimulator on MMP-1 expression by U937 cells. Furthermore, results showed that high glucose, IL-6 and LPS stimulated MMP-1 expression by 1.4-, 3.9-, 6.1-fold, respectively, after 24 h treatment, but the combination of high glucose, IL-6 and LPS led to a 53.3-fold increase, revealing a remarkable synergistic effect between high glucose, IL-6, and LPS on MMP-1 expression. In the studies to elucidate how high glucose and IL-6 act synergistically for MMP-1 upregulation, we found that while either high glucose or IL-6 increased c-Jun expression by 2.5-fold, the combination of high glucose and IL-6 stimulated c-Jun expression by 5-fold. In contrast, high glucose did not enhance IL-6-stimulated c-Fos expression. These results suggest that high glucose and IL-6 exert synergy on MMP-1 expression by upregulating c-Jun, an immediate early gene and a major subunit for transcription factor AP-1 that is known to play a key role in MMP-1 transcription. Our further studies showed that the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways, but not Janus kinases /signal transducer and activator of transcription (JAK/STAT)3 cascade, were involved in high glucose and IL-6-stimulated MMP-1 expression. Taken together, this study showed that high glucose and IL-6 synergistically stimulate MMP-1 expression in U937 mononuclear cells through c-Jun and ERK and JNK cascades.
This work was supported by Merit Review Grant from Department of Veterans Affairs and NIH grant DE16353 (to Y.H.).Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine,College of Medicine. Poster design by Lisa M. Fennessy, MUSC Art Services.