The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis
The functionally important NF-κB1 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-stimul...
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/14/7559 |
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| author | Britta Marko Paulina Heurich Patrick Thon Frieda Zimmer Lars Bergmann Hartmuth Nowak Katharina Rump Björn Koos Michael Adamzik Matthias Unterberg Tim Rahmel |
| author_facet | Britta Marko Paulina Heurich Patrick Thon Frieda Zimmer Lars Bergmann Hartmuth Nowak Katharina Rump Björn Koos Michael Adamzik Matthias Unterberg Tim Rahmel |
| author_sort | Britta Marko |
| collection | DOAJ |
| description | The functionally important NF-κB1 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 (<i>n</i> = 20) and septic patients (<i>n</i> = 10). All individuals were genotyped for the −94ins/delATTG NF-κB1 promoter polymorphism. We found a diminished nuclear activity of the NF-κB subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes (<i>p</i> = 0.025). This was associated with higher TNF-α (<i>p</i> = 0.005) and interleukin 6 concentrations (<i>p</i> = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes (<i>p</i> = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content (<i>p</i> = 0.046) and lower mtDNA copy numbers (<i>p</i> = 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-κB subunits in sepsis. We showed here that the deletion allele of the NF-κB1 (−94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction. |
| first_indexed | 2024-03-09T13:43:23Z |
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| language | English |
| last_indexed | 2024-03-09T13:43:23Z |
| publishDate | 2022-07-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8ba61d4acffc4acfa074b4daae15f0202023-11-30T21:03:43ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012314755910.3390/ijms23147559The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in SepsisBritta Marko0Paulina Heurich1Patrick Thon2Frieda Zimmer3Lars Bergmann4Hartmuth Nowak5Katharina Rump6Björn Koos7Michael Adamzik8Matthias Unterberg9Tim Rahmel10Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyKlinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, In der Schornau 23-25, D-44892 Bochum, GermanyThe functionally important NF-κB1 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 (<i>n</i> = 20) and septic patients (<i>n</i> = 10). All individuals were genotyped for the −94ins/delATTG NF-κB1 promoter polymorphism. We found a diminished nuclear activity of the NF-κB subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes (<i>p</i> = 0.025). This was associated with higher TNF-α (<i>p</i> = 0.005) and interleukin 6 concentrations (<i>p</i> = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes (<i>p</i> = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content (<i>p</i> = 0.046) and lower mtDNA copy numbers (<i>p</i> = 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-κB subunits in sepsis. We showed here that the deletion allele of the NF-κB1 (−94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction.https://www.mdpi.com/1422-0067/23/14/7559nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cellsNF-κBNF-κB1 promoter polymorphismsubunit p50sepsismitochondrial dysfunction |
| spellingShingle | Britta Marko Paulina Heurich Patrick Thon Frieda Zimmer Lars Bergmann Hartmuth Nowak Katharina Rump Björn Koos Michael Adamzik Matthias Unterberg Tim Rahmel The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis International Journal of Molecular Sciences nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells NF-κB NF-κB1 promoter polymorphism subunit p50 sepsis mitochondrial dysfunction |
| title | The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis |
| title_full | The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis |
| title_fullStr | The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis |
| title_full_unstemmed | The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis |
| title_short | The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis |
| title_sort | pro inflammatory deletion allele of the nf κb1 polymorphism is characterized by a depletion of subunit p50 in sepsis |
| topic | nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells NF-κB NF-κB1 promoter polymorphism subunit p50 sepsis mitochondrial dysfunction |
| url | https://www.mdpi.com/1422-0067/23/14/7559 |
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