PROPIONATE REDUCES THE CYTOKINE-INDUCED VCAM-1 AND ICAM-1 EXPRESSION BY INHIBITING NUCLEAR FACTOR-ε B (NF-κB) ACTIVATION

Adhesion and migration of leukocytes into the surrounding tissue arc crucial steps in inflammation, immunity and atherogenesis. Expression of cell adhesion molecules by endothelial cells plays a role in these processes. Propionate is a naturally occurring short chain fatty acid produced by bacterial fermentation of dietary fibre. High intake of dietary fibre has been associated with an improved bowel function and with a reduced risk of cardiovascular disease. However, the molecular mechanisms responsible for these effects remain unknown. In this study, the effects of propionate on the expression of endothelial leukocyte adhesion molecules by cytokine-stimulated human umbilical vein endothelial cells (HUVEC) were investigated. Pretreatment of HUVEC with propionate significantly inhibited the tumor necrosis factor-alpha (TNF-alpha)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in a time- and dose-dependent manner. At 10 mM, propionate also inhibited the interleukin-1 (IL-1)-mediated VCAM-1 and ICAM-1 expression, with the latter effect being more pronounced, as well as decreased the TNF-alpha-induced VCAM-I and ICAM-1 mRNA expression in a similar manner. The decrease in VCAM-l and ICAM-1 expression was associated with a reduction of adherence of monocytes and lymphocytes to the cytokine-stimulated HUVEC. In addition, propionate significantly inhibited the TNF-alpha-induced activation of nuclear factor-kappa B (NF-kappa B) and significantly increased the expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in HUVEC. These results demonstrate that propionate may have anti inflammatory and possibly antiatherogenic properties. Our findings warrant further investigation into the therapeutic effects of propionate on a number of pathological events involving leukocyte recruitment.