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Journal of Cellular Biochemistry

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

Authors

  • Yanchun Li,

    1. Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425
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  • Devadoss J. Samuvel,

    1. Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425
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  • Kamala P. Sundararaj,

    1. Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425
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  • Maria F. Lopes-Virella,

    1. Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401
    2. Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425
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  • Yan Huang

    Corresponding author
    1. Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401
    2. Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425
    • Ralph H. Johnson Veterans Affairs Medical Center, and Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 114 Doughty St. Charleston, SC 29403.
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  • Yanchun Li and Devadoss J. Samuvel contributed equally to this study.

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. J. Cell. Biochem. 110: 248–259, 2010. © 2010 Wiley-Liss, Inc.

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