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Britta Marko, Paulina Heurich, Patrick Thon, Frieda Zimmer, Lars Bergmann, Hartmuth Sebastian Burkhard Nowak, Katharina Rump, Björn Koos, Michael Adamzik, Matthias Unterberg, Tim Rahmel

• The functionally important NF-\(\kappa\)B1 promoter polymorphism (−94ins/delATTG) significantly shapes inflammation and impacts the outcome of sepsis. However, exploratory studies elucidating the molecular link of this genotype-dependent pattern are lacking. Accordingly, we analyzed lipopolysaccharide-stimulated peripheral blood mononuclear cells from both healthy volunteers (\(\it n\) = 20) and septic patients (\(\it n\) = 10). All individuals were genotyped for the −94ins/delATTG NF-\(\kappa\)B1 promoter polymorphism. We found a diminished nuclear activity of the NF-\(\kappa\)B subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes (\(\it p\) = 0.025). This was associated with higher TNF-α (p = 0.005) and interleukin 6 concentrations (p = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes (\(\it p\) = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content (\(\it p\) = 0.046) and lower mtDNA copy numbers (\(\it p\) = 0.010) compared to II genotypes. Strikingly, these findings were mirrored in peripheral blood mononuclear cells taken from septic patients. Our results emphasize the crucial aspect of considering NF-\(\kappa\)B subunits in sepsis. We showed here that the deletion allele of the NF-\(\kappa\)B1 (−94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction.