High glucose-boosted inflammatory responses to lipopolysaccharide are suppressed by statin

• Published in: Journal of periodontal research Vol. 42; no. 1; pp. 31 - 38
• Main Authors: Nareika, A., Maldonado, A., He, L., Game, B. A., Slate, E. H., Sanders, J. J., London, S. D., Lopes-Virella, M. F., Huang, Y.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2007; Blackwell
• Subjects: Biological and medical sciences; Chemokines - antagonists & inhibitors; Chemokines - secretion; Cytokines - antagonists & inhibitors; Cytokines - drug effects; Dentistry; diabetes mellitus; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Facial bones, jaws, teeth, parodontium: diseases, semeiology; Fenofibrate - pharmacology; glucose; Glucose - administration & dosage; Glucose - pharmacology; Histiocytes - drug effects; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hypoglycemic Agents - pharmacology; Hypolipidemic Agents - pharmacology; Inflammation Mediators - metabolism; lipopolysaccharide; Lipopolysaccharides - pharmacology; Medical sciences; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - metabolism; Non tumoral diseases; Otorhinolaryngology. Stomatology; periodontal diseases; Peroxisome Proliferator-Activated Receptors - agonists; Simvastatin - pharmacology; Thiazolidinediones - pharmacology; Time Factors; U937 Cells; Endocrinopathy; glucose: lipopolysaccharide; Stomatology; Diabetes mellitus; Inflammation; Statin derivative; Dentistry; Glucose; Periodontal disease; Lipopolysaccharide; Periodontopathy; periodontal diseases; Antilipemic agent
• ISSN: 0022-3484; 1600-0765
• DOI: 10.1111/j.1600-0765.2006.00911.x

Background and Objective:  It has been established that periodontal diseases are more prevalent and of greater severity in diabetic patients than in nondiabetic patients. Recent studies have underscored the role of monocytes and macrophages in periodontal tissue inflammation and destruction in diabetic patients. Although it has been shown that monocytes isolated from diabetic patients produce more inflammatory cytokines and that gingival crevicular fluid collected from diabetic patients contains higher levels of inflammatory cytokines than that obtained from nondiabetic patients, the underlying mechanisms are not well understood.
Material and Methods:  U937 histiocytes cultured in medium containing either normal (5 mM) or high (25 mM) glucose were treated with 100 ng/ml of lipopolysaccharide for 24h. After the treatment, cytokines in the medium and cytokine mRNA in the cells were quantified using enzyme‐linked immunosorbet assay and real‐time polymerase chain reaction, respectively.
Results:  In this study, we demonstrated that the pre‐exposure of U937 histiocytes to high glucose concentrations markedly increased the lipopolysaccharide‐induced secretion of pro‐inflammatory cytokines and chemokines and the cellular inducible nitric oxide level compared with pre‐exposure to normal glucose. Our data also showed that the increased secretion of cytokines was a result of increased mRNA expression. Furthermore, the effects of statin and peroxisome proliferators‐activated receptor agonists on high glucose‐enhanced secretion of cytokines were determined. The results showed that simvastatin, but not fenofibrate or pioglitazone, inhibited high glucose‐enhanced cytokine release.
Conclusion:  This study has shown that high glucose concentrations and lipopolysaccharide act synergistically to stimulate the secretion of inflammatory mediators, and that statin is capable of suppressing the high glucose‐boosted proinflammatory response. This study therefore delineates a novel mechanism by which hyperglycemia enhances the inflammatory responses of macrophages and suggests that statin may be useful in the treatment of periodontal disease in diabetic patients.