whereas there is no IL-15 mRNA demonstrable in normal Metabolism Branch, National Cancer Institute resting or activated T cells as assessed by Northern blot National Institutes of Health analysis. Nevertheless, there is widespread expression Bethesda, Maryland 20892 of IL-15 message, which appears most abundantly in placenta and skeletal muscle but also in kidney, lung, and heart as well as lipopolysaccharide (LPS)-activated Intercellular communications essential for regulatory monocytes Bamford et al., 1996). and effector actions involved in immune responses areThe expression of the cytokine IL-2 is controlled preoften mediated by a series of proteins termed cytokines.dominantly at the level of transcription and message Cytokines exhibit a high degree of redundancy and stabilization. In contrast, the synthesis and secretion of pleiotropy, controlling a wide range of functions in vari-IL-15 appears to be controlled at multiple levels (e.g., ous cell types. The redundancy is explained in part by translation, and entry into secretory pathway) in addition the promiscuity of receptors; that is, by the sharing of to transcription (Bamford et al., 1996). An additional difcommon receptor subunits among members of the cytoference between IL-15 and IL-2 is that IL-15 uses a kine receptor family (Bazan, 1990;Sato and Miyajima, distinct receptor and signaling system in select cells. In 1994; Kishimoto et al., 1994). Each cytokine has its own particular, IL-15 stimulates the proliferation of mast cells private receptor but may also share a public receptor that do not respond to IL-2 (Tagaya et al., 1996). In with other cytokines. For example, receptors for insuch cells, IL-15 binding and signaling involves a novel terleukin-6 (IL-6), leukemia inhibitory factor, oncostatin receptor system that does not share any subunits with M, ciliary neurotropic factor, IL-11, and cardiotropin-1 the IL-2R system. Furthermore, this novel IL-15R system share a gp130 signaling unit, whereas IL-3, IL-5, and utilizes a signal transduction pathway distinct from the granulocyte/macrophage colony-stimulating factor utione used by the IL-2/IL-15R system in T cells. lize a common ␤c receptor subunit (Sato and Miyajima 1994, Kishimoto et al. 1994). There is a similar sharing Discovery of IL-15 of receptor elements within the IL-2 receptor (IL-2R) IL-15 was discovered because of the capacity of culture system, a system that involves ␣, ␤, and ␥ subunits supernatants from two cell lines, CV-1/EBNA and the (Noguchi et al., 1993a;Kondo et al., 1993). This sharing HTLV-1-associated HuT-102, to stimulate proliferation of IL-2R subunits was anticipated by the initially paraof the cytokine-dependent murine T cell line CTLL-2 doxical observations that the immune system of mice (Burton et al., 1994;Bamford et al., 1994; Grabstein et made deficient in IL-2 by homologous recombination al., 1994). The HTLV-1-associated HuT-102 adult T cell developed relatively normally during the first few weeks leukemia cell line was shown to secrete a 14-15 kDa of life, wherea...

Background Accurate risk assessment of atherosclerotic cardiovascular disease (ASCVD) is essential to effectively balance the risks and benefits of therapy for primary prevention. Objective To compare the calibration and discrimination of the new American Heart Association (AHA) and American College of Cardiology (ACC) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score. Design Prospective epidemiologic study of ASCVD. Setting MESA (Multi-Ethnic Study of Atherosclerosis), a community-based, sex-balanced, multiethnic cohort. Patients 4227 MESA participants aged 50 to 74 years and without diabetes at baseline. Measurements Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores—and their respective end points—in MESA after a 10.2-year follow-up. Results The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37% to 154% in men and 8% to 67% in women. Overestimation was noted throughout the continuum of risk. In contrast, the Reynolds Risk Score overestimated risk by 9% in men but underestimated risk by 21% in women. Aspirin, lipid-lowering or antihypertensive therapy, and interim revascularization did not explain the overestimation. Limitation Comparability of MESA with target populations for primary prevention and possibility of missed events in MESA. Conclusion Of the 5 risk scores, 4, including the new AHA-ACC-ASCVD score, showed overestimation of risk (25% to 115%) in a modern, multiethnic cohort without baseline clinical ASCVD. If validated, overestimation of ASCVD risk may have substantial implications for individual patients and the health care system. Primary Funding Source National Heart, Lung, and Blood Institute.