Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages:: Implications for atherogenesis

Although considerable evidence implicates the cytokine interferon (IFN)-gamma in atherogenesis, the proximal inducers and the range of sources of its expression remain unknown. This study tested the hypothesis that interleukin (IL)-18 regulates IFN-gamma expression during atherogenesis. Indeed, human atheroma in situ expressed IL-18 and elevated levels of its receptor subunits, IL-18Ralpha/beta, compared with nondiseased arterial tissue. IL-18 occurred predominantly as the mature, 18-kD form and colocalized with mononuclear phagocytes (MO), while endothelial cells (ECs), smooth muscle cells (SMCs), and MO all expressed 1L-18Ralpha/beta. Correspondingly in vitro, only MO expressed IL-18, while all three cell types displayed the IL-18Ralpha/beta complex constitutively, exhibiting enhanced expression upon stimulation with LPS, IL-1beta, or tumor necrosis factor (TNF)-alpha. IL-18 signaling evoked effectors involved in atherogenesis, e.g., cytokines (IL-6), chemokines (IL-8), intracellular adhesion molecules (ICAM)-1, and matrix metalloproteinases (MMP-1/-9/-13), demonstrating functionality of the receptor on ECs, SMCs, and MO. Finally, IL-18, particularly in combination with IL-12, induced the expression of IFN-gamma in cultured MO and, surprisingly, in SMCs (but not in ECs). The expression of functional IL-18 and IL-18 receptor on human atheroma-associated ECs, SMCs, and MO, and its unexpected ability to induce IFN-gamma expression in SMCs, suggests a novel paracrine proinflammatory pathway operating during atherogenesis.