Statins potently reduce the cytokine‐mediated IL‐6 release in SMC/MNC cocultures

Inflammatory pathways are involved in the development of atherosclerosis. Interaction of vessel wall cells and invading monocytes by cytokines may trigger local inflammatory processes. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are standard medications used in cardiovascular diseases. They are thought to have anti‐inflammatory capacities, in addition to their lipid‐lowering effects. We investigated the anti‐inflammatory effect of statins in the cytokine‐mediated‐interaction‐model of human vascular smooth muscle cells (SMC) and human mononuclear cells (MNC). In this atherosclerosis‐related inflammatory model LPS (lipopolysaccharide, endotoxin), as well as high mobility group box 1 stimulation resulted in synergistic (i.e. over‐additive) IL‐6 (interleukin‐6) production as measured in ELISA. Recombinant IL‐1, tumour necrosis factor‐α and IL‐6 mediated the synergistic IL‐6 production. The standard anti‐inflammatory drugs aspirin and indomethacin (Indo) reduced the synergistic IL‐6 production by 60%. Simvastatin, atorvastatin, fluvastatin or pravastatin reduced the IL‐6 production by 53%, 50%, 64% and 60%, respectively. The inhibition by the statins was dose dependent. Combination of statins with aspirin and/or Indo resulted in complete inhibition of the synergistic IL‐6 production. The same inhibitors blocked STAT3 phosphorylation, providing evidence for an autocrine role of IL‐6 in the synergism. MNC from volunteers after 5 day aspirin or simvastatin administration showed no decreased IL‐6 production, probably due to drug removal during MNC isolation. Taken together, the data show that anti‐inflammatory functions (here shown for statins) can be sensitively and reproducibly determined in this novel SMC/MNC coculture model. These data implicate that statins have the capacity to affect atherosclerosis by regulating cytokine‐mediated innate inflammatory pathways in the vessel wall.