How steroids switch off inflammation: rewinding DNA
Treating asthma: when steroid receptors (dyed fluorescent) move from the cytoplasm (Cy) into the nucleus (N) of cells that line the lung, inflammatory genes are switched off
Professor Peter Barnes, Dr Ian Adcock and Dr Kazuhiro Ito.
Imperial College London.
More than 5 million people in Britain suffer from the debilitating and sometimes fatal effects of asthma. The disease results from chronic inflammation of the tissues lining the lungs and is usually treated with drugs called corticosteroids, which suppress inflammation. However, scientists know little about how the genes that cause inflammation in lung cells are switched on, or exactly how corticosteroids switch them off again.
Now, a team of researchers at the National Heart and Lung Institute at Imperial College in London have made a surprising discovery about how inflammatory genes get switched on, and how corticosteroids help to switch them off. It seems that inflammation results from changes to the structure of DNA in lung cells. The discovery could lead to new and improved anti-inflammatory drugs, as well as offering new insights into other chronic inflammatory diseases such as rheumatoid arthritis.
The DNA inside living cells rarely takes the form of the naked double helix discovered by Watson and Crick. Instead, it is wound around packaging proteins called histones, which help to protect it, and then parcelled up neatly into chromosomes. Recently, researchers have discovered that histones are not just packaging; they can also affect how genes encoded in the DNA get switched on or off. They do this by controlling how tightly the DNA is wound around them.
'In the resting state, the DNA is very tightly wound,' explains Professor Peter Barnes, who heads the project. When a gene is switched on, the stretch of DNA in which it lies becomes partly unwound from around the histones. This allows the machinery in the cell that turns the gene's instructions into proteins to gain access to the DNA and read it. A collection of enzymes regulates the winding and unwinding by altering the shapes of the histones.
Professor Barnes and his team have discovered that in chronic inflammatory conditions such as asthma, the unwinding enzymes are abnormally active. As a result, DNA containing more than 100 genes involved in causing inflammation gets unwound and switched on.