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Title: The mechanism of Th17 cells induction and its role in the atherosclerotic plaque development
Author: Mohamed, Rafeezul
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 2013
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Atherosclerosis is a chronic inflammatory disease regulated by T-cell subsets. Recently, Th17 cells have been shown to be critical in exacerbating atherosclerosis in humans and mice. Possible mechanisms of Th17 cell differentiation from mouse CD4+ T-cells via oxLDL-treated dendritic cells (DCs) and smooth muscle cells (SMCs) were investigated. The possibility of direct interaction of oxLDL with Th17 cells followed by the effect of Th17 cells induction in vivo on the atherosclerotic plaque development in apoE-/- were examined. It was demonstrated that an atherogenic stimuli, oxLDL induced maturation of DCs by up-regulating the expression of maturation markers CD40, CD86 and MHC class II which facilitated the differentiation of CD4+ T-cells into Th17 cells. The addition of IL-6 and TGF-β during CD4+ T-cells co-cultured with oxLDL-treated DCs increased the expression of IL-17A on CD4+RORyt+ expressing cells. On the other hand, Mitomycin C (MMC) treatment on oxLDL-treated DCs and co-cultured with CD4+ T-cells reduced the expression of IL-17A on CD4+RORyt+ expressing cells. The current study also showed that oxLDL induced the secretion of IL-6, TGF-β and IL-23 by SMCs after 24 hours of incubation. Exogenous IL-6 and TGF-β increased IL-17A expression on CD4+CD25- expressing cells and also IL-17F expression on both CD4+CD25-expressing cells and CD4+RORyt+ expressing cells when CD4+ T-cells co-cultured with oxLDL-treated SMCs. We then investigated the possible direct interaction between oxLDL with Th17 cells. The results showed that treated Th17 cells induced expression of CD36. The current study also demonstrated that treated Th17 cell induced culture also increased the expression of p-STAT-3 and secretion of Th17 cell related cytokines, IL-17A and IL-17F. Finally, the current study demonstrated that pertussis toxin (PTx), anti-CD25 (PC61) and a combination of both treatments increased Th17 cells in the splenocytes of female apoE-/- mice fed with high fat diet (HFD). The serum cholesterol also was significantly higher in the treated mice. Furthermore, the plaque size significantly increased in mice that were treated with PC61 and combinations of PTx and PC61, but no changes were observed in the collagen content. Taken together, the findings suggest that the level of IL-6 and TGF-β secreted by oxLDL-treated DCs and SMCs may influence Th17 cell differentiation. The possible engagement of oxLDL by Th17 cells via CD36 may activate STAT-3, which in turn may mediate the release of IL-17A and IL-17F. The induction of Th17 cells following respective treatments in the apoE-/- mice fed with HFD displayed close correlation between high cholesterol levels and thus increase atherosclerotic plaque development. Therefore, Th17 cells may be a potential target for modulation of atherogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available