Dominance of macrophage derived IFN-γ in atheromatous lesions (35.3)

Abstract

Abstract IFN-γ activates macrophages that are abundant in atheromas, periodontal lesions, and other sites of chronic inflammation. It is thought that the IFN-γ present in athromas is derived from Th-1 cells. However, macrophages dominate the inflammatory infiltrate in atheromas and macrophages can produce IFN-γ prompting the hypothesis that macrophages are the source of a significant proportion of IFN-γ in established atherosclerotic lesions. To test this, CD14+, CD3+, and CD14- & 3- cells were isolated from endarterectomy tissue and examined for spontaneous production of IFN-γ, IL-1β, IL-6, and TNF-α in supernatant fluids from 48 hr cell cultures. The CD14+ macrophages, including foam cells, were responsible not only for the TNF-α, IL-1β & IL-6 but also for the vast majority of the IFN-γ produced in culture. Moreover, this spontaneous macrophage IFN-γ response was maintained in culture for over two weeks. IL-12 induced IFN-γ responses in macrophages and IL-12 was induced by incubating DCs with A. actinomycetemcomitans and far more dramatically by opsonized A. actinomycetemcomitans. In short, engagement of DCs in the intima of the arterial wall with opsonized microorganisms from the blood could trigger IL-12 production, and the released IL-12 could induce a sustained IFN-γ response by macrophages. This macrophage INF-γ response induced by DC-IL-12 bypasses a need for T cells to produce IFN-γ in established atheromas.