Objective-The proatherogenic effect of IL-18 is shown to be dependent on IFN-␥ production. It is believed that activated T cells play a proatherogenic role through secretion of IFN-␥. However, recent studies in vitro have shown that macrophages, NK cells, and even vascular smooth muscle cells may also secrete IFN-␥ after stimulation by cytokines like IL-18. We therefore investigated whether cells other than activated T cells can play a proatherogenic role via IFN-␥ secretion under the stimulation of IL-18 in vivo. Methods and Results-SCID/apoE knockout mice were injected intraperitoneally with either IL-18 or phosphate-buffered saline 3 times per week for 7 weeks. Our results show that administration of IL-18 leads to 3-fold larger lesions and 2-fold higher circulating IFN-␥ despite the absence of T cells. In addition, increased IFN-␥, accompanied by elevation of the scavenger receptor/chemokine CXCL16, was observed in both lesions and spleens.

SUMMARYApolipoprotein E (ApoE) is synthesized by a variety of cells including macrophages. These cells activate T lymphocytes by antigen presentation, while the T-cell cytokine, interferon-g, inhibits macrophage ApoE expression. ApoE inhibits T-cell proliferation in culture but its role in immune responses has been unclear. The ApoE-deficient (E 0 ) mouse permits an evaluation of the immunological role of ApoE. We have analysed T-cell responses to an exogenous antigen (ovalbumin) and polyclonal mitogen (concanavalin A) in E 0 and ApoE þ/þ mice. Macrophages of E 0 mice stimulated T-cell activation more effectively as antigen-presenting cells than macrophages from ApoE þ/þ mice. Both proliferation and interferon-g secretion were enhanced in T cells activated in the context of antigen-presenting cells from E 0 mice. Since the macrophage-T-cell interaction depends on interactions between cell surface molecules, we assessed the expression of such molecules after in vivo stimulation with interferon-g. This treatment caused an increased expression of the co-stimulatory surface proteins CD40 and CD80, and also of the major histocompatibility complex class II molecules I-A b on macrophages of E 0 mice compared with ApoE þ/þ . Our data suggest that ApoE inhibits T-cell activation by reducing the density of immune stimulatory proteins on antigen-presenting cells.

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