Suppression of LPS-induced matrix-metalloproteinase responses in macrophages exposed to phenytoin and its metabolite,5-(p-hydroxyphenyl-), 5-phenylhydantoin

Journal of Inflammation

Research

Nikola Angelov¹  Salvador Nares²  Ryan Serra²  Abdel-ghany Al-saidi² 

[1] Department of Periodontics, School of Dentistry, Loma Linda University, 92350, Loma Linda, CA, USA;Department of Periodontology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA;

关键词: Gingival Crevicular Fluid;    Gingival Fibroblast;    Periodontal Pathogen;    TIMP Level;    Aggregatibacter Actinomycetemcomitans;   

DOI  :  10.1186/1476-9255-7-48

 received in 2010-04-30, accepted in 2010-09-15,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundPhenytoin (PHT) has been reported to induce gingival (gum) overgrowth (GO) in approximately 50% of patients taking this medication. While most studies have focused on the effects of PHT on the fibroblast in the pathophysiology underlying GO, few studies have investigated the potential regulatory role of macrophages in extracellular matrix (ECM) turnover and secretion of proinflammatory mediators. The aim of this study was to evaluate the effects of PHT and its metabolite, 5-(p-hydroxyphenyl-), 5-phenylhydantoin (HPPH) on LPS-elicited MMP, TIMP, TNF-α and IL-6 levels in macrophages.MethodsHuman primary monocyte-derived macrophages (n = 6 independent donors) were pretreated with 15-50 μg/mL PHT-Na+ or 15-50 μg/mL HPPH for 1 hour. Cells were then challenged with 100 ng/ml purified LPS from the periodontal pathogen, Aggregatibacter actinomycetemcomitans. Supernatants were collected after 24 hours and levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TNF-α and IL-6 determined by multiplex analysis or enzyme-linked immunoadsorbent assay.ResultsA dose-dependent inhibition of MMP-1, MMP-3, MMP-9, TIMP-1 but not MMP-2 was noted in culture supernatants pretreated with PHT or HPPH prior to LPS challenge. MMP-12, TIMP-2, TIMP-3 and TIMP-2 were not detected in culture supernatants. High concentrations of PHT but not HPPH, blunted LPS-induced TNF-α production although neither significantly affected IL-6 levels.ConclusionThe ability of macrophages to mediate turnover of ECM via the production of metalloproteinases is compromised not only by PHT, but its metabolite, HPPH in a dose-dependent fashion. Further, the preferential dysregulation of macrophage-derived TNF-α but not IL-6 in response to bacterial challenge may provide an inflammatory environment facilitating collagen accumulation without the counteracting production of MMPs.

【 授权许可】

Unknown   
© Serra et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.