ROLE OF CYTOKINES AND GROWTH FACTORS ON THE PATHOGENESIS OF XANTHOMA

获得了两种氧化修饰的LDL。一种是从兔黄色瘤组织中提取的LDL组分，另一种是与兔黄色瘤组织孵育的人血清LDL。这些LDL已被证明是氧化修饰的。体外诱导人血单核细胞和U-937细胞向巨噬细胞分化。用EASLA法测定巨噬细胞培养液中IL-1、IFN-γ、TNF-α和GM-CSF的含量。两种氧化修饰的LDL均抑制巨噬细胞IL-1的合成，刺激IFN-γ的合成，而对TNF-α的合成无影响。这些发现表明，氧化LDL处理的巨噬细胞不被刺激合成黄瘤促进细胞因子（IL-1和TNF-α），而被刺激合成黄瘤保护细胞因子（IFN-γ）。另一方面，黄瘤组织修饰的LDL刺激巨噬细胞合成促进GM-CSF的黄瘤。人脐静脉内皮细胞（HUVEC）与黄瘤组织修饰的LDL孵育后，用抗ICAM-1、抗VCAM-1和抗ELAM-1抗体进行免疫组化染色，用流式细胞术检测HUVEC上ICAM-1、VCAM-1和ELAM-1的表达。LDL刺激HUVEC后，VCAM-1和ELAM-1呈剂量依赖性表达，而ICAM-1未见表达。这些结果表明，氧化LDL直接诱导内皮细胞表达VCAM-1或ELAM-1，其介导血液单核细胞与内皮细胞的粘附。在粘附分子表达细胞中没有显示NFkB活化。

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.