Type 2 Diabetes (T2D) is an important disorder that represents one of the most serious healthcare challenges facing the world. An estimated 293 million people worldwide are expected to have the condition by the year 2020. T2D is associated with increased cardiovascular and atherosclerotic risk, which are themselves due to increased levels of inflammation present in the disease. Inflammation in T2D is associated with the production of Advanced Glycation End-Products (AGEs), a result of chronically increased blood glucose levels. Clinical studies have demonstrated that the majority of diabetics suffer from cardiovascular disease, which accounts for 80% of all diabetic deaths. The peroxisome proliferator receptors (PPARs), an important group of nuclear receptors are members of the steroid and thyroid hormone receptor family of transcription factors and are increasingly seen as targets in the management of T2D. The dietary polyunsaturated fatty acid, Conjugated Linoleic Acid (CLA) has received considerable attention due to its anti-diabetes and anti-inflammatory effects. CLA has binding affinity for both PPAR-α and -γ and may influence both the cardiovascular risk associated with T2D and also the risk of developingT2D. This study investigated the role of CLA in regulating the inflammatory response of human monocytes. Inflammation was induced using glycated-BSA (Gly-BSA), an Amadori product that consists of 95% protein with 1-5 moles of hexose (as fructosamine) per mole albumin. Gly-BSA acts in a similar way to AGEs to activate monocytes/macrophages by binding to a surface receptor called RAGE. Stimulation of RAGE by gly-BSA leads to activation of a signal transduction pathway, which results in subsequent production of inflammatory cytokines, including Tumour Necrosis Factor -α. Treatment with CLA at a concentration of 60µM significantly reduced (p<0.001, ANOVA) gly-BSA stimulated production of Tumour Necrosis Factor-α, Interleukin-lß, Prostaglandin E2 and Cyclooxygenase-2 by the human monocytic cell-line MM6. CLA was found to modulate the activity of both the nuclear transcription factor NF-KB and RAGE in these cells. Treating MM6 cells with antisense oligonucleotide to PPAR-α and also to PPAR-γ revealed that the modulatory effects of CLA were mediated through PPAR-α but not PPAR-γ. In contrast, CLA treatment did not reduce gly-BSA stimulated Tumour Necrosis Factor-α and RAGE expression in another human monocytic/macrophage cell line, differentiated THP-1 macrophages and also in human-peripheral blood monocyte derived macrophages. The increase in RAGE expression and TNF-α secretion by CLA in these macrophages appeared to be mediated through both PPAR-γ and PPAR-α mediated mechanisms. Taken together these findings indicate CLA can interfere with the inflammatory processes of monocytic cell lines; and that both down-regulation and up-regulation of inflammatory processes by CLA are cell-specific, and mediated via both PPAR-γ and PPAR-α.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:629875 |
| Date | January 2005 |
| Creators | Lin, Thet Thet |
| Publisher | Cardiff Metropolitan University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10369/6415 |
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