The significance of lipopolysaccharide in hygiene hypothesis: Regulation of proallergic cytokines in respiratory epithelial cells
| Autor: | Tsang Hsiung Lin, 林滄雄 |
|---|---|
| Rok vydání: | 2018 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 106 Epidemiological studies based on the “hygiene hypothesis” declare that the level of childhood exposure to environmental microbial products is inversely related to the incidence of allergic diseases in later life. The higher level of environmental lipopolysaccharide (LPS) children exposed to, the lower the incidence of later allergic diseases. Another study focusing on the common cold also concluded that more runny nose episodes in infancy protect against later atopy. However, the mechanisms of protection, the nature of protective infections and the target cells of protective infections were not previously clear. Previous studies were focused on dendritic cells, but the effects of the microbial products on dendritic cells cannot fully explain the mechanism of hygiene hypothesis. Epithelial cells are the first line of response to microbial products in the environment and bridge the innate and adaptive immune systems; however, their role in the hygiene hypothesis is unknown. Our study revealed that LPS(ligand of the TLR 4) attenuates the induction of proallergic cytokines, mainly thymic stromal lymphopoietin (TSLP) and IL33 in H292 cells (a mucosal epidermoid carcinoma cell line of lung) that is stimulated by polyinosinic:polycytidylic acid (polyI: C) and human parechovirus 1 (HPeV1). Stimulation with the TLR3 ligand polyI:C and human parechovirus type 1 (HPeV1), but not LPS induce the production of TSLP and IL33 by H292 cells through interferon regulatory factor 3 (IRF3) and NF-κB activity, and leads to Th2 response. The pathway was further validated by using inhibitors (dexamethasone and Bay 11-7082) and short hairpin RNA-mediated gene knockdown. Importantly, polyI:C and HPeV1-stimulated TSLP and IL33 induction was reduced by LPS treatment by attenuating TBK1, IRF3, and NF-κB activation. Interestingly, the basal mRNA levels of TLR signaling proteins were downregulated with long-term LPS treatment of H292 cells, which suggests that such long-term exposure modulates the expression of innate immunity signaling molecules in airway epithelial cells to mitigate the allergic response. While polyI: C and HPeV1 stimulate the dendritic cells, it can induce a Th1 response. Our findings propose an in vitro respiratory epithelial cell model comprising four players, which can explain most of the mechanism of the hygiene hypothesis. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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