Hydrocortisone Fails to Abolish NF-κB1 Protein Nuclear Translocation in Deletion Allele Carriers of the NFKB1 Promoter Polymorphism (-94ins/delATTG) and Is Associated with Increased 30-Day Mortality in Septic Shock

Background: Previous investigations and meta-analyses on the effect of glucocorticoids on mortality in septic shockrevealed mixed results. This heterogeneity might be evoked by genetic variations. Such candidate is a promoterpolymorphism (-94ins/delATTG) of the gene encoding the ubiquitous transcription-factor nuclear-factor-kB (NF-kB) whichbinds to recognition elements in the promoter of several genes encoding for the innate immune-system. In turn,hydrocortisone inhibits NF-kB nuclear translocation and thus transcription of key immune-response regulators. Accordingly,we tested the hypotheses that hydrocortisone has aNFKB1genotype dependent effect on 1) NF-kB1 nuclear translocationevoked by lipopolysaccharide (LPS) in monocytesin vitro, and 2) mortality in septic shock.

Methods: Monocytes of volunteers with the homozygous insertion (II; n = 5) or deletion (DD; n = 6)NFKB1genotype wereincubated with 10mgml-1LPS6hydrocortisone (10-5M), and NF-kB1 nuclear translocation was assessed (immunofluo-rescence). Furthermore, we analyzed 30-day-mortality in 160 patients with septic shock stratified for both genotype andhydrocortisone therapy.

Results: Hydrocortisone inhibited LPS induced nuclear translocation of NF-kB1 in II (25%611;p = 0.0001) but not in DDgenotypes (51%615;p = n.s.). Onehundredandfour of 160 patients with septic shock received hydrocortisone, at thediscretion of the intensivist.NFKB1deletion allele carriers (ID/DD) receiving hydrocortisone had a much greater 30-day-mortality (57.6%) than II genotypes (24.4%; HR:3.18, 95%-CI:1.61-6.28;p = 0.001). In contrast, 30-day mortality was 22.2% inID/DD and 25.0% in II genotypes without hydrocortisone therapy. Results were similar when using propensity scorematching to account for possible bias in the intensivists’ decision to administer hydrocortisone.

Conclusion: Hydrocortisone fails to inhibit LPS induced nuclear NF-kB1 translocation in deletion allele carriers of theNFKB1promoter polymorphism (-94ins/delATTG). In septic shock, hydrocortisone treatment is associated with markedly increased30-day-mortality only in such carriers. Accordingly, previous heterogeneous results regarding the benefit of hydrocortisonein septic shock may be reconciled by genetic variation of theNFKB1promoter polymorphism.

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Schäfer, S.T., Gessner, S., Scherag, A., Rump, K., Frey, U.H., Siffert, W., Westendorf, A.M., Steinmann, J., Peters, J., Adamzik, M., 2014. Hydrocortisone Fails to Abolish NF-κB1 Protein Nuclear Translocation in Deletion Allele Carriers of the NFKB1 Promoter Polymorphism (-94ins/delATTG) and Is Associated with Increased 30-Day Mortality in Septic Shock. https://doi.org/10.1371/journal.pone.0104953
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