Localization of T lymphocytes and macrophages expressing IL-1, IL-2 receptor, IL-6 and TNF in human aortic intima. Role of cell-mediated immunity in human atherogenesis

Abstract

Recent observations have demonstrated the presence of activated T lymphocytes and macrophages in human atherosclerotic lesions. Cells found within these lesions produce cytokines that alter vascular homeostasis in a manner that promotes atherogenesis. To elucidate the role of these immunocompetent cells in human atherosclerosis, the localization of various cytokines with an analysis of immunophenotypic features of the cellular infiltrates was studied in normal aortas from children; and in later phases of the disease (including fatty streaks and fibrous or atheromatous plaques). Semi-quantitative analysis of cytokine-expressing cells was also investigated with serial sectioning. In 4 of 9 young subjects, the grossly normal aorta contained relatively cell-rich areas which were located preferentially around the ostia of intercostal arteries and were composed of isolated or layered T lymphocytes and macrophages. In these prelesional areas, interleukin-1 (IL-1), IL-2 receptor (IL-2R) and tumour necrosis factor (TNF) were detected in the cytoplasm of the infiltrating cells, whereas no detectable reactivity was noted for IL-2, IL-6, interferon-gamma (IFN-gamma) or lymphotoxin (LT). In fatty streaks and full-grown atheromas including "cap" and "shoulder" regions, various numbers of T lymphocytes, macrophages and macrophage foam cells were present. In these lesion areas, especially where the cellular infiltrates were numerous, macrophage foam cells and smooth muscle cells expressed not only IL-1 and TNF but also IL-6. The ratio of IL-2R positive cells showed a tendency to decrease with advance of the disease process. Electron-microscopic examination of lesion areas demonstrated ultrastructural aspects of the cognate cell-to-cell interaction, as shown by the direct apposition of lymphocytes to macrophages or macrophage foam cells. These results suggest that a specific in situ, cell mediated hypersensitivity plays a pivotal role in the nascent as well as the progression stages of human atherosclerosis.

Systemic Inflammatory Parameters in Patients With Atherosclerosis of the Coronary and Peripheral Arteries

“…62 For example, studies by Wick and others have found evidence of inflammatory activity with cellular infiltrates in the arteries of children and young adults before the development of atherosclerosis. [63][64][65] Conversely, the increased level of parameters of inflammation may contribute directly to atherogenesis. CRP has been shown to increase the opsonization and uptake of lipid complexes by macrophages, 66 and SAA modifies HDL particles such that their affinity for monocytes/macrophages is increased.…”

Expression of Interleukin-6 in Atherosclerotic Lesions of Male ApoE-Knockout Mice

“…These 2 experiments established that the amount of IL-6 mRNA and protein is substantially increased in the vascular lesions of the apoE-KO mouse, similar to that observed in humans. 4,5 We also evaluated the relationship between the extent of plaque in an isolated aorta segment and the amount of IL-6 secreted from the same tissue. We observed a significant, positive, linear relationship between these 2 variables in male apoE-KO mice between the ages of 6 and 48 weeks.…”

“…4 This observation has been confirmed and extended by immunohistochemical studies that have demonstrated colocalized IL-6 protein expression with macrophages as well as smooth muscle cells in human atherosclerotic plaques. 5 Moreover, IL-6 has been shown to have important effects on the cell types that are components of atherosclerotic lesions. IL-6 can "prime" THP-1 macrophage cells to produce enhanced amounts of tumor necrosis factor-␣ in response to lipopolysaccharide (LPS), 6 suggesting that IL-6 may play a role in stimulating macrophages to attain their full inflammatory potential.…”

Costimulatory molecules in human atherosclerotic plaques: an indication of antigen specific T lymphocyte activation

“…Activated (HLA-DR + ) macrophages and HLA-DR + /IL-2R + T lymphocytes are present in fatty streaks and fully developed atherosclerotic plaques [3][4][5]. Expression of MHC class II antigens by macrophages in atherosclerotic lesions suggests that these cells present antigen to T lymphocytes.…”