IL‐6 and high glucose synergistically upregulate MMP‐1 expression by U937 mononuclear phagocytes via ERK1/2 and JNK pathways and c‐Jun

Abstract

Matrix metalloproteinases (MMPs) play a pivotal role in tissue remodeling and destruction in inflammation-associated diseases such as cardiovascular disease and periodontal disease. Although it is known that interleukin (IL)-6 is a key proinflamatory cytokine, it remains unclear how IL-6 regulates MMP expression by mononuclear phagocytes. Furthermore, it remains undetermined how IL-6 in combination with hyperglycemia affects MMP expression. In the present study, we investigated the regulatory effect of IL-6 alone or in combination with high glucose on MMP-1 expression by U937 mononuclear phagocytes. We found that IL-6 is a powerful stimulator for MMP-1 expression and high glucose further augmented IL-6-stimulated MMP-1 expression. We also found that high glucose, IL-6, and lipopolysaccharide act in concert to stimulate MMP-1 expression. In the studies to elucidate underlying mechanisms, the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways were found to be required for stimulation of MMP-1 by IL-6 and high glucose. We also observed that IL-6 and high glucose stimulated the expression of c-Jun, a key subunit of AP-1 known to be essential for MMP-1 transcription. The role of c-Jun in MMP-1 expression was confirmed by the finding that suppression of c-Jun expression by RNA interference significantly inhibited MMP-1 expression. Finally, we demonstrated that similarly to U937 mononuclear phagocytes, IL-6 and high glucose also stimulated MMP-1 secretion from human primary monocytes. In conclusion, this study demonstrated that IL-6 and high glucose synergistically stimulated MMP-1 expression in mononuclear phagocytes via ERK and JNK cascades and c-Jun upregulation. KeywordsMatrix metalloproteinases; Interleukin 6; Diabetes; Mitogen-activated protein kinases Interleukin-6 (IL-6) is a multifunctional cytokine involved in the acute phase response, immunity, hematopoiesis, and inflammation [Ishihara and Hirano, 2002;Kishimoto, 2006]. IL-6 plays an essential role in many chronic inflammatory diseases such as rheumatoid arthritis, systemic-onset juvenile chronic arthritis, osteoporosis, psoriasis, and autoimmune diseases such as antigen-induced arthritis and experimental allergic encephalomyelitis [Ishihara and Hirano, 2002]. IL-6 is also important in the pathogenesis of infectious diseases such as periodontal disease [Geivelis et al., 1993;Rusconi et al., 1991]. Furthermore, IL-6 is a marker for cardiovascular disease [Kristiansen and Mandrup-Poulsen, 2005;Rattazzi et al., 2003], which is considered as an inflammatory disease. Studies have well documented that the plasma levels of IL-6 and C-reactive protein are strong independent predictors of risk of future cardiovascular events, both in patients with a history of coronary heart disease and in apparently healthy subjects [Rattazzi et al., 2003]. Numerous studies have further demonstrated that IL-6 is not just a marker for inflammation-associated diseases; it is a major player involved in the initiation and progression of the d...

Insulin treatment attenuates diabetes-increased atherosclerotic intimal lesions and matrix metalloproteinase 9 expression in apolipoprotein E-deficient mice

“…Our laboratory showed that high glucose increased the expression of c-Jun and c-Fos, which are the major subunits of AP-1 transcription factor (Li et al 2010). Given that AP1 is a key transcription factor for MMP9 expression (Aljada et al 2001), it is most likely that high glucose stimulates MMP9 expression by increasing AP1 level.…”

“…They found that although serum cholesterol, low-density lipoprotein, C-reactive protein, and carotid atheromatous plaques were reduced in patients treated with statins, CD68-positive cells were increased in atherosclerotic lesions. Furthermore, they found that the expression of IL6, a major proinflammatory cytokine expressed by macrophages (Li et al 2010), was lower in atherosclerotic plaques in patients treated with statins. This study suggests that statin treatment attenuates macrophage activation, but not the recruitment of macrophages.…”

“…8A) have provided evidence indicating the effect of multiple stimulators on MMP9 upregulation. Since IL6 also increased c-Jun and c-Fos expression (Li et al 2010), it is likely that high glucose and IL6 synergistically increase MMP9 expression by their coordinate action on AP1 activity.…”

“…It is known that IL6 is expressed in atherosclerotic plaques and involved in MMP expression (Li et al 2010). To determine the effect of diabetes and insulin treatment on the expression of IL6, we assessed IL6 expression in atherosclerotic lesions by immunohistochemistry.…”

Acid sphingomyelinase plays a key role in palmitic acid-amplified inflammatory signaling triggered by lipopolysaccharide at low concentrations in macrophages

“…IL-6 increases matrix degradation by stimulating matrix metalloproteinase expression and promotes bone loss by increasing osteoclastogenesis and reducing osteoblast activity (34). IL-6 is promptly and highly responsive to inflammatory stimuli, as its expression rises rapidly and robustly and reaches the peak in a few hours (1).…”