Macrophage-specific inhibition of NF-κB activation reduces foam-cell formation

Accumulation of lipid-laden macrophages is a hallmark of atherosclerosis. The relevance of the key transcription factor nuclear factor kappa B (NF-kappa B) for macrophage-derived foam-cell formation has not been unequivocally resolved. Transgenic mice lines were generated in which NF-kappa B activation is specifically inhibited in macrophages by overexpressing a trans-dominant, non-degradable form of I kappa B alpha (I kappa B alpha (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-kappa B/I kappa B alpha (32A/36A) complex in the cytoplasm. Similarly, stable human THP1 monocytic cell lines were generated with integrated copies of I kappa B alpha (32A/36A) cDNA. Upon treatment with oxidized low-density lipoprotein (ox-LDL), murine peritoneal macrophages from transgenic I kappa B alpha (32A/36A) mice, as well as THP1/I kappa B alpha (32A/36A) clones, display decreased lipid loading after differentiation into macrophages. This is accompanied, by increased expression of the transcription factors PPAR gamma and LXR alpha 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-kappa B activation, ABCAI-mediated cholesterol efflux prevails over CD36-mediated lipid influx. (c) 2006 Elsevier Ireland Ltd. All rights reserved.