The anti-atherogenic cytokine interleukin-33 inhibits the expression of a disintegrin and metalloproteinase with thrombospondin motifs-1, -4 and -5 in human macrophages: Requirement of extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphoinositide 3-kinase signaling pathways☆

Atherosclerosis is an inflammatory disorder of the vasculature regulated by cytokines. Amongst the cytokines, IL-33 attenuates the development of atherosclerosis in mouse model systems via several mechanisms, including inhibition of macrophage foam cell formation and promotion of a Th1 to Th2 shift. Proteases produced by macrophages, such as matrix metalloproteinases and members of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family, play potential roles in regulating atherosclerotic plaque stability. Despite such importance, the action of IL-33 on the expression of such proteases has not been analyzed. We have therefore investigated the effect of IL-33 on the expression of ADAMTS-1, -4 and -5 in human macrophages. Immunohistochemical analysis showed that these three proteases were expressed in human atherosclerotic lesions, particularly by macrophages and, to a lesser extent, by smooth muscle cells and endothelial cells. The expression of ADAMTS-1, -4 and -5 in human macrophages was specifically inhibited by IL-33. The action of IL-33 on the expression of these ADAMTS members was mediated through its receptor ST2. IL-33 activated ERK1/2, JNK1/2 and c-Jun, but not p38 MAPK or Akt, in human macrophages. RNA interference assays using a combination of adenoviral encoding small hairpin RNA and small interfering RNA showed a requirement of ERK1/2, JNK1/2, c-Jun, PI3Kγ and PI3Kδ, but not p38α, in the IL-33-inhibited expression of these ADAMTS isoforms. These studies provide novel insights into the expression of ADAMTS-1, -4 and -5 in human atherosclerotic lesions and the regulation of their expression in human macrophages by the key anti-atherogenic cytokine IL-33.