ORIGINAL ARTICLE Heart Vessels (2003) 18:183–187 © Springer-Verlag 2003 DOI 10.1007/s00380-003-0719-7 Minako Yamaoka-Tojo · Taiki Tojo · Takashi Masuda Yoji Machida · Yoshikazu Kitano · Toshirou Kurosawa Tohru Izumi C-reactive protein-induced production of interleukin-18 in human endothelial cells: a mechanism of orchestrating cytokine cascade in acute coronary syndrome Received: December 19, 2002 / Accepted: May 17, 2003 M. Yamaoka-Tojo (*) 1 · T. Tojo · T. Masuda · Y. Machida · Y. Kitano · T. Kurosawa · T. Izumi Department of Internal Medicine and Cardiology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan Present address: 1 Division of Cardiology, Emory University School of Medicine, 1639 Pierce Drive, WMB Room 325, Atlanta, GA 30322, USA Tel. +1-404-727-3126; Fax +1-404-727-3330 e-mail: myamaoka-circ@umin.ac.jp Abstract The circulating interleukin (IL)-18 level is a strong predictor of death from cardiovascular causes in pa- tients with coronary artery disease. However, the mecha- nisms of IL-18 in orchestrating the cytokine cascade and the accelerator of IL-18 production in atherosclerosis are still unknown. In the present study, we measured the serum concentration of IL-18 and other markers of inflammation in 35 patients with acute coronary syndrome. To determine the mechanism of accelerating IL-18 production, we exam- ined the release of IL-18 in human endothelial cells using human recombinant (hr) C-reactive protein (CRP) as a stimulator of IL-18. Furthermore, we investigated the in- hibitory effects of hr IL-10 on IL-18 production by hr CRP in human endothelial cells. Circulating levels of IL-18 were significantly higher in patients with acute myocardial infarc- tion than in patients with unstable angina. Incubation with hr CRP, which was equivalent to the serum concentration in patients with acute coronary syndrome, induced IL-18 re- lease. Treatment with hr IL-10 inhibited IL-18 release in the cells stimulated with hr CRP. The serum level of IL-18 was identified as a marker of severity in acute coronary syn- drome. Our findings reveal the possibility that circulating CRP by itself could cause a deterioration of the inflam- matory cascade in endothelial cells associated with the upregulation of IL-18. This suggests that CRP may contrib- ute to the mechanism of coronary artery disease in addition to being an incidental product of various types of systemic inflammation. Key words Interleukin-18 · C-reactive protein · Acute coro- nary syndrome Introduction Chronic inflammation causes atherosclerosis 1 and is also involved in atherosclerotic plaque disruption and thrombo- sis, and may greatly influence the occurrence of acute ischemic syndrome. Current research has mostly focused on C-reactive protein (CRP) as a marker for coronary heart disease and acute coronary syndrome, but CRP itself might also directly provide a proinflammatory stimulus. 2 Interleukin (IL)-18, originally termed interferon (IFN)-γ- inducing factor, is a newly discovered cytokine with pleio- tropic activities extending from Th1 polarization of the immune response to a proinflammatory activity. 3,4 The mul- tifunctional properties of IL-18 production in numerous diseases, such as infections, several types of cancer, and in-inflammatory and autoimmune diseases, reflect an inappropriate immune response. 5–7 A recent study showed significant expression of IL-18 in human carotid atheroscle- rotic plaques. 8 Increasing plasma levels of IL-18 in patients with acute coronary syndrome were reported to the associ- ated with increased mortality. 9 Moreover, the serum IL-18 level was identified as a strong independent predictor of death from cardiovascular causes in patients with coronary artery disease. 10 However, the effects of IL-18 on the pro- duction of other cytokines in coronary artery disease are still unknown. We hypothesized that IL-18 could upregulate excessive expression of inflammatory properties, and might play an important role in atherosclerosis development and stability in patients with acute coronary syndrome. In the present study, we evaluated the serum concentration of IL- 18 in patients with acute coronary syndrome. Furthermore, we tested the hypothesis that CRP can be a trigger of IL-18 expression in human endothelial cells and that this mecha- nism is inhibited by IL-10 in vivo. Thus, CRP might provide a trigger for elevated IL-18 levels in acute coronary syndrome.