Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.
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.
Pathan
Nazima
N
Department of Paediatrics, Imperial College of Science, Technology and Medicine, W2 1PG, London, UK. n.pathan@imperial.ac.uk
Hemingway
Cheryl A
CA
Alizadeh
Ash A
AA
Stephens
Alick C
AC
Boldrick
Jennifer C
JC
Oragui
Emmanuelle E
EE
McCabe
Colm
C
Welch
Steven B
SB
Whitney
Adeline
A
O'Gara
Peter
P
Nadel
Simon
S
Relman
David A
DA
Harding
Sian E
SE
Levin
Michael
M
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*
D016207:Cytokines; D015850:Interleukin-6; D009201:Myocardial Depressant Factor