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¹ Ralph H Johnson Veterans Affairs Medical Center, ² Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine³ Department of Biostatistics, Bioinformatics and Epidemiology and ⁴ College of Dental Medicine, Medical University of South Carolina, Charleston, 114 Doughty Street, South Carolina 29401, USA

(Correspondence should be addressed to Y Huang; Email: huangyan{at}musc.edu)

We have demonstrated recently that high glucose augments lipopolysaccharide (LPS)-stimulated matrix metalloproteinase (MMP) and cytokine expression by U937 mononuclear cells and human monocyte-derived macrophages. Since CD14 is a receptor for LPS, one potential underlying mechanism is that high glucose enhances CD14 expression. In the present study, we determined the effect of high glucose on CD14 expression by U937 mononuclear cells. After being chronically exposed to normal or high glucose for 2 weeks or longer, cells were treated with LPS for 24 h. Real-time PCR showed that although high glucose by itself did not increase CD14 expression significantly, it augmented LPS-stimulated CD14 expression by 15-fold. Immunoassay showed a marked enhancement of both membrane-associated and soluble CD14 protein levels by high glucose. Further investigations using transcription factor activity assays and gel shift assays revealed that high glucose augmented LPS-stimulated CD14 expression by enhancing transcription factor nuclear factor B (NFB) and activator protein-1 (AP-1) activities. Finally, studies using anti-CD14 neutralizing antibody showed that CD14 expression is essential for the enhancement of LPS-stimulated MMP-1 expression by high glucose. Taken together, this study has demonstrated a robust augmentation by high glucose of LPS-stimulated CD14 expression through AP-1 and NFB transcriptional activity enhancement, elucidating a new mechanism by which hyperglycemia boosts LPS-elicited gene expression involved in inflammation and tissue destruction.

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				K. P. Sundararaj, D. J. Samuvel, Y. Li, J. J. Sanders, M. F. Lopes-Virella, and Y. Huang Interleukin-6 Released from Fibroblasts Is Essential for Up-regulation of Matrix Metalloproteinase-1 Expression by U937 Macrophages in Coculture: CROSS-TALKING BETWEEN FIBROBLASTS AND U937 MACROPHAGES EXPOSED TO HIGH GLUCOSE J. Biol. Chem., May 15, 2009; 284(20): 13714 - 13724. [Abstract] [Full Text] [PDF]