Accumulation of lipid-laden macrophages is a hallmark of atherosclerosis. The relevance of the key transcription factor nuclear factor kappaB (NF-kappaB) for macrophage-derived foam-cell formation has not been unequivocally resolved. Transgenic mice lines were generated in which NF-kappaB activation is specifically inhibited in macrophages by overexpressing a trans-dominant, non-degradable form of IkappaBalpha (IkappaBalpha (32A/36A)) under control of the macrophage-specific SR-A promoter. Alanine substitution of serines 32 and 36 prevents degradation and retains the inactive NF-kappaB/IkappaBalpha (32A/36A) complex in the cytoplasm. Similarly, stable human THP1 monocytic cell lines were generated with integrated copies of IkappaBalpha (32A/36A) cDNA. Upon treatment with oxidized low-density lipoprotein (ox-LDL), murine peritoneal macrophages from transgenic IkappaBalpha (32A/36A) mice, as well as THP1/IkappaBalpha (32A/36A) clones, display decreased lipid loading after differentiation into macrophages. This is accompanied by increased expression of the transcription factors PPARgamma and LXRalpha as well as of the major cholesterol-efflux transporter ABCA1. Paradoxically, mRNA expression of the 'lipid-uptake' receptor CD36 is also increased. Since the net result of these changes is reduction of foam-cell formation, it is proposed that under specific inhibition of NF-kappaB activation, ABCA1-mediated cholesterol efflux prevails over CD36-mediated lipid influx.

译文

:富含脂质的巨噬细胞的积累是动脉粥样硬化的标志。尚未明确解决关键转录因子核因子κB(NF-κB)与巨噬细胞衍生的泡沫细胞形成的相关性。通过在巨噬细胞特异性SR-A启动子的控制下过表达不可表达形式的IkappaBalpha(IkappaBalpha(32A / 36A)),从而在巨噬细胞中特异性抑制NF-κB活化的转基因小鼠品系。丝氨酸32和36的丙氨酸取代防止降解并在细胞质中保留无活性的NF-κB/IκBα(32A / 36A)复合物。类似地,用整合的IkappaBalpha(32A / 36A)cDNA拷贝产生稳定的人THP1单核细胞系。经氧化低密度脂蛋白(ox-LDL)处理后,转基因IkappaBalpha(32A / 36A)小鼠以及THP1 / IkappaBalpha(32A / 36A)克隆的小鼠腹膜巨噬细胞在分化为巨噬细胞后显示出降低的脂质负载。这伴随着转录因子PPARgamma和LXRalpha以及主要胆固醇外流转运蛋白ABCA1的表达增加。矛盾的是,“脂质摄取”受体CD36的mRNA表达也增加了。由于这些变化的最终结果是减少了泡沫细胞的形成,因此建议在特定抑制NF-κB活化的情况下,ABCA1介导的胆固醇外排比CD36介导的脂质内流更为普遍。

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