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dc.contributor.authorBostanci, Nagihan
dc.date.accessioned2011-07-22T16:17:49Z
dc.date.available2011-07-22T16:17:49Z
dc.date.issued2007
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/1419
dc.descriptionPhDen_US
dc.description.abstractThere is good evidence that interleukin-I alpha (IL-Ia) plays a key role in both the host response to bacteria and the tissue destruction associated with periodontal disease. This thesis investigated the interaction of bacterial, genetic and pharmacological factors in the regulation of IL-la in periodontal disease. To investigate the stimulation of IL-la by periodontal pathogens, human monocytes were challenged with a wide range of periodontal species. Most of the species tested stimulated high levels of IL-la. Induction by P. gingivalis was notably weak. Co-stimulation with P. gingivalis antagonised the ability of other bacterial species to induce IL-la, and this antagonism was due to the specific nature of its LPS. The association of periodontal. disease with host genetic variation was investigated by screening the IL-lA promoter region by direct sequencing in patients with aggressive periodontitis. Three single-nucleotide polymorphisms (SNPs) were identified including rs3783521 C>T, rs1800794 C>T, rs1800587 C>T. However, the prevalence of polymorphic alleles between patients and healthy subjects was similar. To test if any of these polymorphisms effect transcription of IL-IA, the polymorphisms of interest were introduced into an IL-lu luciferase reporter construct by site-directed mutagenesis. Only one of these polymorphisms, rs1800587 (-899), resulted in a significant change in transcription using transient transfection assays. The T allele of this SNP reduced both the basal activity and the response to LPS or periodontopathogens. Therefore, the rs1800587 SNP might play a role in the regulation of IL-lA gene transcription induced by bacteria. The central role played by IL-1 a in the pathogenesis of periodontal disease suggests that immunomodulation may offer a therapeutic option. Sub-antimicrobial concentrations of doxycycline inhibited IL-Ict production in response to bacterial stimulation by human monocytes. This effect appears to be at translational level rather than transcription. It does not appear to involve the regulation of NF-icB activity, or the suppression of IL-Ict transcription, or doxycycline chelation properties. In conclusion, IL-la is a pivotal cytokine involved in periodontal disease, and its regulation is a complex event governed by bacterial factors, host genetics and pharmacological agents.en_US
dc.language.isoenen_US
dc.subjectMedicineen_US
dc.titleInterleukin-1[Alpha] production in periodontal disease: the interaction of bacteria and gene polymorphisms.en_US
dc.typeThesisen_US
dc.rights.holderThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author


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    Theses Awarded by Queen Mary University of London

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