Interleukin-1[Alpha] production in periodontal disease: the interaction of bacteria and gene polymorphisms.
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There 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.
Authors
Bostanci, NagihanCollections
- Theses [4359]