Ding, Cherlyn (2011) Effects of calcitriol on the crosstalk between macrophages and human adipocytes. Masters thesis, University of Liverpool.
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Macrophage-infiltration of adipocytes in obesity provides an important mechanistic link that may explain the increase in inflammatory mediators produced by adipose tissue. Elucidating the crosstalk mechanisms between macrophages and adipocytes is important as adipose tissue has been shown to be the linchpin linking inflammation and insulin resistance. Growing evidence suggests that vitamin D exerts immunomodulatory effects and adipose tissue could be a target for its action. This study investigated the role of vitamin D3 (calcitriol) in alleviating inflammation mediators expressed and released by human adipocytes under the basal and stimulated conditions. The study also examined the effect of calcitriol on monocyte migration as well as on the NF-κB and MAPK signalling pathways. A simulated model of adipocyte inflammation was created by incubating adipocytes with macrophage-conditioned (MC) medium, and this model was then used to study the effect of vitamin D. High dose calcitriol (10-8M) decreased the basal levels of MCP-1 and IL-6 released by adipocytes. Pretreatment with calcitriol (10-8M) reduced the rise in protein levels of MCP-1 and IL-6 released by adipocytes after stimulation with MC medium. Calcitriol (10-8M) also decreased IL-6 release but it had no effect on MCP-1 production by adipocytes stimulated with TNF-α. Upon MC medium stimulation, calcitriol (10-8M) partially reversed the decrease in gene expression of adiponectin and ZAG although the release of adiponectin or ZAG by adipocytes was unaffected. In addition, calcitriol (10-11M and 10-8M) supplementation decreased THP-1 macrophage migration although it did not reverse the effects of MC medium or TNF-α. Furthermore, calcitriol increased the basal protein abundance of NF-κB IκBα and reversed the inhibitory effect of MC medium on IκBα. Calcitriol supplementation also decreased both basal and MC medium stimulated protein abundance of phosphorylated NF-κB p65 as well as basal and MC medium stimulated levels of phosphorylated p38 MAPK. In conclusion, this study has shown that MC medium potently stimulated inflammatory responses in human adipocytes. Calcitriol supplementation was able to reduce the basal and stimulated production of the proinflammatory mediators by adipocytes. Calcitriol also led to a decrease in chemoattractant ability of adipocytes. In addition, calcitriol exhibited an inhibitory effect on the activation of the NF-κB and MAPK signalling pathways. These results suggest that calcitriol may have a beneficial effect in protecting against adipose tissue inflammation induced by the crosstalk between macrophages and adipocytes.
|Item Type:||Thesis (Masters)|
|Departments, Research Centres and Related Units:||Academic Faculties, Institutes and Research Centres > Faculty of Medicine > School of Clinical Sciences|
|Deposited On:||08 Aug 2012 12:15|
|Last Modified:||08 Aug 2012 12:15|
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