Cardiovascular Drug Discovery & Therapy (Track)


Daryn R. Michael, James E. McLaren, Na Li, Rebecca C. Salter, Tim G. Ashlin, Melanie L. Buckley and Dipak P. Ramji

Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff, UK


Atherosclerosis is an inflammatory disorder orchestrated by cytokines. The transformation of macrophages into foam cells is a critical early step in atherosclerosis. The action of different cytokines on macrophage foam cell formation is poorly understood and was therefore investigated using both classical cytokines, such as interferon-g (IFN-g) and transforming growth factor-b (TGF-b), and those identified more recently, such as tumour necrosis factor-like protein 1A (TL1A) and interleukin-33 (IL-33). The cytokines IFN-γ and TL1A induced foam cell formation by stimulating the uptake of modified lipoproteins and inhibiting the efflux of cholesterol. Extracellular signal-regulated kinase was integral to the action of IFN-γ. TGF-β and IL-33, on the other hand, inhibited foam cell formation by suppressing the uptake of modified lipoproteins and storage of cholesterol, and stimulating the intracellular trafficking and efflux of this sterol. Consistent with these findings, TGF-β and IL-33 decreased the expression of several key genes implicated in the uptake of modified lipoproteins and, simultaneously, induced those implicated in the transport of cholesterol from the cytosol to the plasma membrane and its subsequent efflux from cells. These studies provide novel insights into the regulation of macrophage cholesterol homeostasis by key cytokines implicated in atherosclerosis.

Funding: British Heart Foundation.