ROLE OF CYTOKINES AND GROWTH FACTORS ON THE PATHOGENESIS OF XANTHOMA

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Two kinds of oxidatively modified LDLs were obtained. One was the LDL fraction extracted from himogenized rabbit xanthoma tissues and the other was human serum LDL which had been incubated with rabbit xanthoma tissues. These LDLs have been revealed to be oxidatively modified. Human blood monocytes and U-937 cell line were differentiated to macrophages in vitro. After an incubation of these macrophages with the two kinds of LDLs, IL-1, IFN-gamma, TNF-alpha and GM-CSF levels in the medium were assayd by the EASLA method. Both two types of oxidatively modified LDLs suppressed the IL-1 synthesis, stimulated the IFN-gamma synthesis and geve no effects on the TNF-alpha synthesis by these macrophages. These findings suggest that oxidized-LDL treated macrophages are not stimulated to synthesize the xanthoma promoting cytokines (IL-1 and TNF-alpha) and are stimulated to synthesize the xanthoma protecting cytokines (IFN-gamma). On the other hand, the synthesis of xanthoma promoting GM-CSF by macrophages are stimulated by these LDLs.Human umbilical vein endothelial cells (HUVEC) were immunohistochemically stained using anti-ICAM-1, anti-VCAM-1 and anti-ELAM-1 antibodies after an incubation with the xanthoma tissue-modified LDL.Expression of ICAM-1, VCAM-1 and ELAM-1 on the HUVEC was investigated by flow cytometry. Both VCAM-1 and ELAM-1 were dose-dependently expressed on the HUVEC by a stimuation with the LDL.On the other hand, ICAM-1 expression was never observed. These results suggest that oxidized LDL directly elicit the endothelial cell expression of VCAM-1 or ELAM-1 which mediate the adhesion of blood monocytes to endothelial cells. NFkB activation in the adhesion molecule expressing cells was not revealed.