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

Abstract 

Accumulation of lipid-laden macrophages is a hallmark of atherosclerosis. The relevance of the key transcription factor nuclear factor κB (NF-κB) for macrophage-derived foam-cell formation has not been unequivocally resolved. Transgenic mice lines were generated in which NF-κB activation is specifically inhibited in macrophages by overexpressing a trans-dominant, non-degradable form of IκBα (IκBα (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-κB/IκBα (32A/36A) complex in the cytoplasm. Similarly, stable human THP1 monocytic cell lines were generated with integrated copies of IκBα (32A/36A) cDNA. Upon treatment with oxidized low-density lipoprotein (ox-LDL), murine peritoneal macrophages from transgenic IκBα (32A/36A) mice, as well as THP1/IκBα (32A/36A) clones, display decreased lipid loading after differentiation into macrophages. This is accompanied by increased expression of the transcription factors PPARγ and LXRα 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-κB activation, ABCA1-mediated cholesterol efflux prevails over CD36-mediated lipid influx.

Abbreviations: ABCA1, ATP binding cassette A1 receptor, ac-LDL, acetylated low-density lipoprotein, FBS, fetal bovine serum, hGH, human growth hormone, IκB, inhibitor of nuclear factor κB, LXRα, liver X receptor α, NF-κB, nuclear factor κB, ox-LDL, oxidized low-density lipoprotein, PMA, phorbol myristate acetate, PPARγ, peroxisome proliferation activation receptor γ, SR-A, scavenger receptor A, Tg, transgenic

Keywords: Foam cell formation, Macrophage specific inhibition of NF-κB, IκBα, ABCA1 mediated cholesterol efflux, ox-LDL-PPARγ-CD36 “feed-forward cycle”