Reddi, Krisanavane; (1995) Modulation of cytokine synthesis by bacterial components. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The chronic inflammatory diseases (CIPDs) are mankind's most prevalent chronic inflammatory conditions. Inflammation in the gingivae is associated with the destruction of the alveolar bone and periodontal ligament which support the teeth. There is good evidence for the involvement of a range of Gram-negative anaerobic and capnophilic bacteria in tissue pathology including: Actinobacillus actinomycetemcomitans, Eikenella corrodens, Porphyromonas gingivalis, Campylobacter rectus and Prevotella intermedia. Invasion of lesional tissues is not a conspicuous feature of this disease and the current paradigm is that soluble components or products of bacteria drive the tissue pathology. However, the nature of these virulence determinants has not been defined. This study has examined the capacity of proteins, associated with the bacterial surface (termed surface-associated material- SAM) and the outer membrane (lipid A-associated proteins-LAP), from these bacteria to stimulate bone resorption and to induce the synthesis of cytokines by myelomonocytic and mesenchymal cell populations. These activities have been compared with those of the lipopolysaccharides from the respective organisms. The bone resorbing activity of the SAMs from the bacteria studied varied widely in potency and efficacy. Some bacteria had SAMs which showed activity at concentrations as low as 1 ng/ml while others required microgram/ml concentrations to produce minimal bone resorption. In contrast, all the LAPs tested showed similar potencies and efficacies. The activity of the LPS from the various organisms was generally low. The capacity of the SAMs to induce the release of the pro-inflammatory cytokines IL-1, IL-6, IL-8 and TNF-α also showed a range of potencies and efficacies. In comparative studies of the cytokine-stimulating actions of the SAMs, LAP and LPS from A. actinomycetemcomitans the former generally showed the greatest potency with the LAP being somewhat less potent and the LPS showing very little activity. Comparison of the mechanism of stimulation of gingival fibroblast IL-6 release by SAMs or E coli LPS revealed major differences. Stimulation by the SAMs was not affected by neutralizing IL-1 or TNF-α activity or by dexamethasone. In contrast LPS-induced IL-6 synthesis was totally abolished by these agents. This suggests that the active cytokine inducing component in the SAM from A. actinomycetemcomitans may interact with a novel transcriptional regulatory site in the IL-6 gene. This active IL-6 stimulating component has been purified by various chromatographic techniques and was found to be a 2 kDa peptide. The results of this study have shown that bacterial components other than LPS are potent inducers of cytokine release and bone resorption in vitro, and so may play a role in initiating the tissue destruction characteristic of periodontitis.

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