sábado, 29 de enero de 2011

White blood cell 'master switch' discovery to aid rheumatoid arthritis treatments

Scientists in the UK have identified a protein that acts as a 'master switch' in certain white blood cells, determining whether they promote or inhibit inflammation. They believe these findings, presented in the journal Nature Immunology, could aid treatments for diseases, such as rheumatoid arthritis, which involve excessive inflammation. The study was funded in part by the MODEL-IN ('Genomic determinants of inflammation: from physical measurements to system perturbation and mathematical') project, which is backed with more than EUR 2.9 million under the EU's Seventh Framework Programme (FP7).
Rheumatoid arthritis suffer with excessive inflammation© ShutterstockWhile inflammatory responses are an important defence that the body uses against harmful stimuli like infections or tissue damage, in many conditions, excessive inflammation can harm the body. For example, rheumatoid arthritis sufferers must contend with joints that become swollen and painful. But the reasons why this happens are not well understood.The research team from Imperial College London (ICL) in the UK explained that immune system cells called macrophages can either stimulate inflammation or suppress it by releasing chemical signals that alter the behaviour of other cells. In their study, the researchers showed that a protein called IRF5 acts as a molecular switch that controls whether macrophages promote or inhibit inflammation.Their finding suggests that blocking the production of IRF5 in macrophages might be an effective way of treating a wide range of autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, lupus, and multiple sclerosis. They explained that boosting IRF5 levels might help treat people whose immune systems are compromised.
Senior researcher Dr Irina Udalova from the Kennedy Institute of Rheumatology at Imperial said: 'Diseases can affect which genes are switched on and off in particular types of cells. Understanding how this switching is regulated is crucial for designing targeted strategies to suppress unwanted cell responses.'According to Dr Udalova, 'Our results show that IRF5 is the master switch in a key set of immune cells, which determines the profile of genes that get turned on in those cells.' She described this finding as 'really exciting because it means that if we can design molecules that interfere with IRF5 function, it could give us new anti-inflammatory treatments for a wide variety of conditions'. Researchers from ICL have previously developed anti-TNF (tumor necrosis factor) treatments, a class of drug that is widely used as a treatment for rheumatoid arthritis. The drugs target TNF, an important signalling chemical released by immune cells to stimulate inflammatory responses.
However, about 30% of patients do not respond to anti-TNF drugs, so there is a serious need to develop more widely effective therapies.Gene association studies have linked variations in the gene that encodes IRF5 with an increased risk of autoimmune diseases. Dr Udalova, therefore, also investigated what role the protein plays in controlling inflammation. She used engineered viruses to introduce extra copies of the IRF5 gene in human macrophages grown in the laboratory, making the cells produce more IRF5. When she did this to macrophages with anti-inflammatory characteristics, it made them switch to promoting inflammation. Blocking IRF5 in pro-inflammatory macrophages using synthetic molecules reduced the cells' production of signals that promote inflammation. She also studied genetically modified mice that were unable to produce IRF5. These mice produced lower levels of chemical signals that stimulate inflammation.
Dr Udalova concluded that IRF5 seems to work by switching on genes that stimulate inflammatory responses and dampening genes that inhibit them. It can either do this by interacting with deoxyribonucleic acid (DNA) directly, or by interacting with other proteins that control which genes are switched on. Her team is now studying how IRF5 works at a molecular level and which other proteins it interacts with in order to design ways to block.

**Published in "Research Information Center"

No hay comentarios: