IL-18 accelerates atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells.

OBJECTIVE: The proatherogenic effect of IL-18 is shown to be dependent on IFN-gamma production. It is believed that activated T cells play a proatherogenic role through secretion of IFN-gamma. However, recent studies in vitro have shown that macrophages, NK cells, and even vascular smooth muscle cells may also secrete IFN-gamma after stimulation by cytokines like IL-18. We therefore investigated whether cells other than activated T cells can play a proatherogenic role via IFN-gamma 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-gamma despite the absence of T cells. In addition, increased IFN-gamma, accompanied by elevation of the scavenger receptor/chemokine CXCL16, was observed in both lesions and spleens. Furthermore, our findings revealed that macrophages, NK cells, and vascular cells were the source of IFN-gamma under the stimulation of IL-18 in the absence of T cells in vivo. CONCLUSIONS: The current data suggest that the proatherogenic effect of IL-18 can occur in the absence of T cells and that IFN-gamma secreted by macrophages, NK cells, and vascular cells is sufficient for the disease progression.

Apolipoprotein E modulates immune activation by acting on the antigen-presenting cell.

Apolipoprotein 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-gamma, inhibits macrophage ApoE expression. ApoE inhibits T-cell proliferation in culture but its role in immune responses has been unclear. The ApoE-deficient (E0) 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 E0 and ApoE+/+ mice. Macrophages of E0 mice stimulated T-cell activation more effectively as antigen-presenting cells than macrophages from ApoE+/+ mice. Both proliferation and interferon-gamma secretion were enhanced in T cells activated in the context of antigen-presenting cells from E0 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-gamma. 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-Ab on macrophages of E0 mice compared with ApoE+/+. Our data suggest that ApoE inhibits T-cell activation by reducing the density of immune stimulatory proteins on antigen-presenting cells.