Macrophage activation is a complex process which is regulated by a large number of extracellular signals. The principal emphasis in analyzing macrophage activation over the past decade has been the elucidation of those signals which induce activation to enhanced microbicidal or tumoricidal function and for other functions, such as presentation of antigen to T-cells. More recently, attention has been focused on regulation of major gene products of macrophages. In particular, increasing emphasis is being placed on defining the mechanisms by which extracellular stimuli or inhibitors alter both gene expression and the complex functions associated with macrophage activation. Bacterial lipopolysaccharides (LPS) have been recognized as a prototypic macrophage activating signal for many years and, as such,have come under intense scrutiny. To date, there is no consensus of the mechanism(s) of transduction initiated by LPS, or which of these events are critical to the subsequent genomic and functional effects. The regulation of an important cytokine, TNF-alpha, falls into this category. Recent evidence suggests a direct role for macrophage activation and cytokine secretion in the pathogenesis of periodontal diseases. From many perspectives, periodontal diseases represent an excellent model for the study of LPS- induced macrophages with respect of TNF-alpha gene regulation as it relates to the activation of other cytokines. Our preliminary data demonstrate that LPS isolated from a major periodontal pathogen, Porphyromonas gingivalis (P.g.) is capable of inducing dose-dependent TNF-alpha production. This induction seems to be mediated through the cell surface membrane receptors, CD-14 molecule, which is serum dependent. At the molecular level,we have sequenced TNF-alpha promoter region in an attempt to locate binding sequences important in TNF-alpha transcription. The specific objectives of this proposal are: 1) to assess the potential of P.g. LPS to induce macrophage TNF-alpha gene expression and secretion; 2) to determine the nuclear cascade of events involved after LPS-induced macrophage activation. Our objective is to prevent the extension of inflammation into the deeper structures of the periodontium and to suppress bursts of TNF-alpha production in periodontal tissues.
| Shapira, L; Champagne, C; Gordon, B et al. (1995) Lipopolysaccharide priming of superoxide release by human neutrophils: role of membrane CD14 and serum LPS binding protein. Inflammation 19:289-95 |
