CDU Contributing Writer
The cytokine interleukin-6 plays an important role in triggering the rapid damage to heart muscle function that can develop in people with septic shock following infection with meningococci, a condition that often is fatal. The team making that discovery says it will be important to investigate IL-6 as a target for therapeutic agents.
Simon Nadel, consultant in pediatric intensive care at St. Mary's Hospital (London), told Cardiovascular Device Update's sister publication, BioWorld International, "One of the key questions now is whether it will be possible to develop new treatments either to suppress the production of interleukin 6, or neutralize it."
Nazima Pathan and colleagues reported their work in a paper in the Jan. 17 issue of The Lancet. Pathan, a clinical research fellow at Imperial College (also London) and the first author of the paper, said: "We were able to rapidly screen the pro-inflammatory response to sepsis on a genome-wide scale, to identify all the mediators conforming to the defined characteristics of the factor that depresses the function of the heart muscle. This led to the finding that interleukin-6 is a major myocardial depressant factor in meningococcal septic shock."
The discovery is the culmination of several decades of research by numerous teams of scientists that have tried to identify the substances that are released into the bloodstream when septic shock develops, damaging the heart muscle's ability to contract. Previous attempts to pin down the molecules responsible had come up with inconclusive data, possibly because there are many different causes of septic shock.
The team led by Michael Levin, which includes clinicians and researchers from St. Mary's Hospital and the UK's National Heart and Lung Institute (London), therefore decided to concentrate on a single cause of septic shock, which normally affects healthy people without other medical or surgical conditions. They focused on meningococcal sepsis, which is the most frequent infectious cause of death in children in the UK, with death often occurring as a result of myocardial failure. That type of heart failure does not respond to conventional treatment. The organs of patients who are severely affected suffer low oxygen levels caused by low blood flow, with subsequent organ failure.
Pathan had shown that if she added plasma taken from children with meningococcal disease to isolated rat myocytes (heart muscle cells), the cells' ability to contract was impaired. She also separated the proteins present in the children's plasma according to size, using chromatography, and worked out the size, molecular weight and charge of the protein present in the fraction that had the observed effect on rat myocytes. Investigations by the team had shown that this protein was released when peripheral blood cells were exposed to meningococci in vitro, with a peak in the amount released at three hours.
The researchers hypothesized that the gene or genes encoding that protein would be up-regulated in peripheral blood cells soon after being exposed to meningococci. They used high-density gene microarray expression profiling to identify the genes, based on what they knew about the size and chemistry of the protein. The experiments allowed them to identify more than 170 genes that became more active following exposure of the blood cells to meningococci. Of them, only six fit their other criteria. Further experiments helped them to eliminate five, IL-6 as the prime suspect.
For their next investigation, they checked the serum concentration of IL-6 in 140 patients admitted with severe meningococcal disease. Patients with more severe disease, and those with greater myocardial dysfunction, were significantly more likely to have higher serum concentrations of the cytokine. In laboratory tests, adding recombinant IL-6 to rat cardiac myocytes reduced the contractility of the cells in the same way as adding meningococcal serum would.
"Future work will clearly need to investigate the mechanisms of interleukin-6-associated cardiac dysfunction in sepsis, and the effects of interleukin-6 reversal," Pathan said. "Clearly, other cytokines, particularly tumor necrosis factor-alpha, may have a synergistic role, but our studies suggest that interleukin-6 is important both by the extremely elevated levels seen in patients with meningococcal shock, by its association with cardiac morbidity, and also by the reversal of cardiac depressant activity when interleukin-6 is removed from meningococcal serum."