title: 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.
abstract: BACKGROUND
  Previous investigations and meta-analyses on the effect of glucocorticoids on mortality in septic shock revealed mixed results. This heterogeneity might be evoked by genetic variations. Such candidate is a promoter polymorphism (-94ins/delATTG) of the gene encoding the ubiquitous transcription-factor nuclear-factor-κB (NF-κB) which binds to recognition elements in the promoter of several genes encoding for the innate immune-system. In turn, hydrocortisone inhibits NF-κB nuclear translocation and thus transcription of key immune-response regulators. Accordingly, we tested the hypotheses that hydrocortisone has a NFKB1 genotype dependent effect on 1) NF-κB1 nuclear translocation evoked by lipopolysaccharide (LPS) in monocytes in vitro, and 2) mortality in septic shock.
  
  
  METHODS
  Monocytes of volunteers with the homozygous insertion (II; n = 5) or deletion (DD; n = 6) NFKB1 genotype were incubated with 10 µgml-1 LPS ± hydrocortisone (10-5M), and NF-κB1 nuclear translocation was assessed (immunofluorescence). Furthermore, we analyzed 30-day-mortality in 160 patients with septic shock stratified for both genotype and hydrocortisone therapy.
  
  
  RESULTS
  Hydrocortisone inhibited LPS induced nuclear translocation of NF-κB1 in II (25%±11;p = 0.0001) but not in DD genotypes (51%±15;p = n.s.). Onehundredandfour of 160 patients with septic shock received hydrocortisone, at the discretion of the intensivist. NFKB1 deletion 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% in ID/DD and 25.0% in II genotypes without hydrocortisone therapy. Results were similar when using propensity score matching to account for possible bias in the intensivists' decision to administer hydrocortisone.
  
  
  CONCLUSIONS
  Hydrocortisone fails to inhibit LPS induced nuclear NF-κB1 translocation in deletion allele carriers of the NFKB1 promoter polymorphism (-94ins/delATTG). In septic shock, hydrocortisone treatment is associated with markedly increased 30-day-mortality only in such carriers. Accordingly, previous heterogeneous results regarding the benefit of hydrocortisone in septic shock may be reconciled by genetic variation of the NFKB1 promoter polymorphism.
authors.affiliation: Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Schäfer
authors.affiliation: Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Gessner
authors.affiliation: Klinische Epidemiologie, Integriertes Forschungs- und Behandlungszentrum (IFB) Sepsis und Sepsisfolgen - Center for Sepsis Control and Care (CSCC), Universitätsklinikum Jena, Jena, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Scherag
authors.affiliation: Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany; Universität Duisburg-Essen and Universitätsklinikum Essen, Essen Germany; Klinik für Anästhesiologie und Intensivmedizin, Knappschaftskrankenhaus Bochum and Ruhruniversität Bochum, Bochum, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rump
authors.affiliation: Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Frey
authors.affiliation: Institut für Pharmakogenetik, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.affiliation: Institut für Medizinische Mikrobiologie. Zurich, Switzerland.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
authors.affiliation: Institut für Medizinische Mikrobiologie. Zurich, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinmann
authors.affiliation: Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Peters
authors.affiliation: Klinik für Anästhesiologie & Intensivmedizin, Universität Duisburg-Essen and Universitätsklinikum Essen, Essen, Germany; Universität Duisburg-Essen and Universitätsklinikum Essen, Essen Germany; Klinik für Anästhesiologie und Intensivmedizin, Knappschaftskrankenhaus Bochum and Ruhruniversität Bochum, Bochum, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Adamzik
mesh_terms: D000368:Aged; D000483:Alleles; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D021381:Protein Transport / Q000187:drug effects*; D012772:Shock, Septic / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D006854:Hydrocortisone