title: Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.
abstract: BACKGROUND
  Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock.
  
  
  METHODS
  We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection.
  
  
  RESULTS
  We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock.
  
  
  CONCLUSIONS
  Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.
authors.affiliation: Department of Paediatrics, Imperial College of Science, Technology and Medicine, W2 1PG, London, UK. n.pathan@imperial.ac.uk
authors.forename: Nazima
authors.initials: N
authors.lastname: Pathan
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hemingway
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Alick C
authors.initials: AC
authors.lastname: Stephens
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Boldrick
authors.forename: Emmanuelle E
authors.initials: EE
authors.lastname: Oragui
authors.forename: Colm
authors.initials: C
authors.lastname: McCabe
authors.forename: Steven B
authors.initials: SB
authors.lastname: Welch
authors.forename: Adeline
authors.initials: A
authors.lastname: Whitney
authors.forename: Peter
authors.initials: P
authors.lastname: O'Gara
authors.forename: Simon
authors.initials: S
authors.lastname: Nadel
authors.forename: David A
authors.initials: DA
authors.lastname: Relman
authors.forename: Sian E
authors.initials: SE
authors.lastname: Harding
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
mesh_terms: D000328:Adult; D000818:Animals; D002303:Cardiac Output, Low / Q000097:blood / Q000503:physiopathology; D009202:Cardiomyopathies / Q000097:blood / Q000503:physiopathology*; D016207:Cytokines / Q000097:blood / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000097:blood / Q000502:physiology*; D008297:Male; D008589:Meningococcal Infections / Q000097:blood / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000502:physiology; D009201:Myocardial Depressant Factor / Q000097:blood / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000097:blood / Q000503:physiopathology*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D009201:Myocardial Depressant Factor