The role of conjugated linoleic acid in regulating the inflammatory response in human monocytic cells

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 80Vo 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 -y 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 957o 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-1β, 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 PPARy

revealed that the modulatory effects of CLA were mediated through PPAR-α but not

PPAR-y. 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-y 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-y and PPAR-α