The prevalence of allergic diseases is increasing worldwide for unclear reasons. This sudden widespread increase, particularly in children, suggests causes that are not due to genetic makeup of individuals, but rather a change in environment and lifestyle factors. Growing epidemiological and immunological evidence supports the hygiene hypothesis, which states that decreased exposure to immune stimulatinginfections in early childhood is the cause of the rise in allergic diseases. Studies have shown that even bacterial components such as lipopolysaccharide (LPS) can have a protective effect. The receptor for LPS is Toll-like receptor 4 (TLR4), an innate immunological receptor, which may play an essential role in regulation of allergic disease. We investigated the expression of TLR4 in the nasal mucosa of allergic and non-allergic children and adults, the effects of LPS on allergic inflammation and the regulation of TLR4 expression. We hypothesized that LPS, through TLR4, could regulate allergic inflammation and that long-term allergic inflammation would limit these responses. / Children and adults undergoing nasal surgery were recruited from the local hospitals. Nasal biopsies from the patients were explanted and cultured ex vivo with allergen and LPS. LPS could prevent allergen-induced Th2 cytokine production and inflammatory cell increases in explants from atopic children; this was through induction of Th1 cytokines and IL-10. TLR4 was also detected on CD4+CD25+ T cells. LPS did not provide the same protection in adults. Adults, especially atopic subjects, had less TLR4 immunopositive cells; hence, their reduced responsiveness to LPS. This suggests that factors could downregulate TLR4 in allergic adults. The U-937 monocytic cell line was used as an in vitro model to study the regulation of TLR4 by interleukin-4 (IL-4), a T-helper type 2 (Th2) cytokine involved in allergic inflammation. U-937 cells cultured with IL-4 had decreased LPS responsiveness, TLR4 protein surface expression, TLR4 mRNA expression and transcriptional activity of the upstream region of TLR4. This effect was tyrosine kinase and STAT6 dependent. A STAT6 binding site was determined in an area of the TLR4 gene necessary to mediate IL-4's inhibitory effects on TLR4 transcription. IL-4 was also determined to reduce TLR4 expression in PBMCs, especially in CD4+ T cells purified from the blood of children. / As predicted in epidemiological studies and animal studies, LPS was shown to provide anti-inflammatory effects against allergen in human nasal tissue. LPS may directly stimulate regulatory T cells (CD25+CD4+) to produce anti-inflammatory cytokine production. The effects of LPS exposure may be lost due to reduced expression of TLR4 by inflammatory cells, and this may be caused by the allergic inflammation itself. Therefore, development of allergic inflammation can down-regulate anti-inflammatory mechanisms and promote long term chronic inflammation.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.100363 |
| Date | January 2006 |
| Creators | Fiset, Pierre-Olivier. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pathology.) |
| Rights | © Pierre-Olivier Fiset, 2006 |
| Relation | alephsysno: 002329577, proquestno: AAINR25145, Theses scanned by UMI/ProQuest. |
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