The association of MMP-9 and IL-18 gene promoter polymorphisms with gingivitis in adolescents
Introduction
Periodontal diseases (gingivitis and periodontitis) are inflammatory processes of the gingival and supporting structures of the teeth induced by a microbial biofilm but individual differences in the host immune response to infection may affect the susceptibility and severity of disease.1, 2 Gingivitis is mainly related to plaque and calculus and leads to a local inflammatory response which, however, is unable to eliminate the microbial products completely and chronic progression may turn into periodontitis. The degradation of collagen fibers and extracellular matrix components results from the activity of matrix metalloproteinases (MMPs).3, 4, 5 MMPs, structural and functional family of proteolytic enzymes, may play an important role in tissue remodeling and repair associated with development of inflammatory response.6, 7 Periodontal disease development and progression can be caused by MMPs produced by both infiltrating and resident cells of the periodontium.3, 8 One of the most important MMPs, MMP-9 (also known as gelatinase B or 92-kD type IV collagenase), is active against collagens and proteoglycans. The coding gene was located on chromosome 20q11.2-q13.1 and several polymorphisms have been detected in the MMP-9 gene. The C to T substitution in position −1562 leads to the loss of a binding of a nuclear protein to this region of the MMP-9 gene promoter and the increase in transcriptional activity in macrophages.9 The individuals carrying the T allele, in compliance with the findings from in vitro experiments, have increased plasma levels of MMP-9.9 Higher levels of the MMP-9 in patients with periodontitis in comparison to the healthy population were also observed.8
Plaque bacteria function as a pool of lipopolysaccharides and activate mononuclear phagocytes, especially macrophages. The macrophages serve as a source of pluripotent proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) or IL-18. Originally, IL-18 was found as an interferon γ-inducing factor (IGIF) that modulates both innate and adaptive immunity.10 As a pleiotropic cytokine induces the production of IL-4, IL-6, IL-13 and histamine, it augments natural killer (NK) activity, and stimulates Fas ligand expression.11 IL-18 directly increases the production of TNF-α and subsequent release of IL-1β and IL-8 from monocytes. The local production of IL-1β and IL-18 in the gingival tissue samples12 or gingival crevicular fluid13 increases with increasing inflammation and IL-18 was the predominant cytokine at both gingivitis and periodontitis sites. Among other functions, regulation of expression of MMP-9 and stimulation of its active form can be mentioned.5, 11, 14 The gene for IL-18 is located on chromosome 11q22.2-q22.3 9 and contains many polymorphic loci, especially in the promoter region.10 Several variants cause differences in transcription factor binding, e.g., a change from C to A at position −607 disrupts a potential binding site for cAMP-responsive element binding protein, while allele C at −137(G/C) has been shown experimentally to disrupt a confirmed H4TF1-binding site.15 In the IL-18 promoter transcription activity assay, Giedraitis et al. (2001) demonstrated low promoter activity following stimulation for both the A and C alleles at positions −607(C/A) and −137(G/C). In additional study, polymorphism at position +183(A/G) was also significantly associated with circulating IL-18 levels, it points toward a potential functional role of this variant.16
With respect to the key role of matrix metalloproteinases and interleukins in inflammatory response in gingivitis, the MMP-9 and IL-18 genes are obvious functional candidates for this disorder. This study was undertaken to compare the distributions of the MMP-9 −1562C/T and IL-18 −607A/C alleles in healthy Czech adolescents aged 11–13 years and in those with plaque-induced gingivitis.
Section snippets
Subjects
The total number of 298 Caucasian adolescents (150 boys and 148 girls) of exclusively Caucasians of Czech nationality, aged 11–13 years, selected from the ELSPAC Brno study (European Longitudinal Study of Pregnancy and Childhood), which comprises over 5000 children and their families, was examined to assess gingival health in this case–control study. The ELSPAC is a prospective study in several European countries where the chosen group of children and their families are examined from pregnancy
Results
The power calculation performed for this study demonstrated that the sample size required to detect significant association of plaque-induced gingivitis with genetic polymorphisms selected with α-value of 0.05, and OR = 1.95 and 65% power was 141 for healthy children and 141 for cases. This shows that our sample size was sufficient to detect association with an acceptable level of significance.
Gingivitis was observed in 147 (49.3%) of the children examined (i.e., cases), the rest of the group was
Discussion
Periodontal diseases are chronic infections characterised by inflammation and destruction of the supporting tissues of the affected teeth. Interaction of various genes and environmental factors play a role in pathogenesis of these disorders.27, 28, 29 External factors (e.g., bacteria, plaque) and diminished host response balance may initiate the periodontal disease. However, the role of environmental factors is clearer than the role of genes; their influence is much harder to measure.30 This
Acknowledgements
The study was supported by the grant IGA NR9129-3/06 and by the project 1M0528.
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