The role of inflammatory mediators in the pathogenesis of periodontal disease

Authors

  • Roy C. Page

    Corresponding author
    1. Research Center in Oral Biology, and the Departments of Periodontics and Pathology, Health Sciences Center, University of Washington, Seattle, WA, U.S.A.
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  • Supported in part by NIHINIDR grants PO1 DE08555 and P50 DE08229.

Roy C. Page Research Center in Oral Biology Health Sciences Center University of Washington Seattle, WA 98195 USA

Abstract

The role of bacteria in the initiation of periodontitis is well-documented and the end result, destruction of the alveolar bone and periodontal connective tissue, is readily observed; but the events occurring between these two points in time remain obscure and are the focus of this paper. Bacteria induce tissue destruction indirectly by activating host defense cells, which in turn produce and release mediators that stimulate the effectors of connective tissue breakdown. Components of microbial plaque have the capacity to induce the initial infiltrate of inflammatory cells including lymphocytes, macrophages, and PMNs. Microbial components, especially lipopolysaccharide (LPS), have the capacity to activate macrophages to synthesize and secrete a wide array of molecules including the cytokines interleukin-1 (IL-1) and tumor-necrosis factor-α (TNF-α), prostaglandins, especially PGE2, and hydrolytic enzymes. Likewise, bacterial substances activate T lymphocytes and they produce IL-1 and lymphotoxin (LT), a molecule having properties very similar to TNF-α. These cytokines manifest potent proinflammatory and catabolic activities, and play key roles in periodontal tissue breakdown. They induce fibroblasts and macrophages to produce neutral metalloproteinases such as procollagenase and prostromelysin, the serine proteinase urokinase-type plasminogen activator (μ-PA), tissue inhibitor of metalloproteinase (TIMP), and prostaglandins. μ-PA converts plasminogen into plasmin, which can activate neutral metalloproteinase proenzymes, and these enzymes degrade the extracellular matrix components. TIMP inactivates the active enzymes and thereby blocks further tissue degradation. Several amplification and suppression mechanisms are involved in the process. While LPS activates macrophages to produce IL-1. IL-1 is autostimulatory and can therefore amplify and perpetuate its own production. Interferon-γ (INF-γ) suppresses autostimulation, but it enhances LPS-induced IL-1 production. PGE2 exerts a control over the whole process by suppressing production of both IL-1 and TNF-α. Furthermore, the activated cells produce an IL-1 receptor antagonist that binds to the IL-1 receptor but does not induce the biologic consequences of IL-1 binding. Other cytokines such as transforming growth factor-β (TGF-β) suppress production of metalloproteinases and μ-PA. Thus the progression and extent of tissue degradation is likely to be determined in major part by relative concentrations and half-life of IL-1, TNF-α, and related cytokines, competing molecules such as the IL-1 receptor antagonist, and suppressive molecules such as TGF-β and PGE2. These molecules control levels of latent and active metalloproteinase and μ-PA, and the availability and concentration of TIMP determines the extent and duration of degradative activity.

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