Scientists who have discovered the mechanism of a protein that suppresses inflammation in the body, say the information could potentially be used to develop new drugs to control inflammation.
The international study, led by a husband-and-wife team, Associate Professor Marcel Nold and Dr Claudia Nold from The Ritchie Centre at MIMR-PHI Institute of Medical Research and Monash University, focused on interleukin 37 (IL-37), a powerful inhibitor of inflammation that is generated by the body.
Previous research by the same team identified that IL-37, one of the rare anti-inflammatory mediators, acts much more broadly than others to regulate the immune response and protect the body from damage.
The new study, published in Nature Immunology, deciphers the mechanisms of how the body uses IL-37 as a molecular signal to regulate and control inflammation.
The team found that to achieve its protective effects, IL-37 utilises a set of very specific receptors on target cells. By binding to these receptors, IL-37 instructs those target cells to execute a cascade of events, which temper several of the molecular pathways by which the body mounts inflammatory responses.
Associate Professor Marcel Nold said inflammation is a double-edged sword.
'We all need inflammation to protect us from the harmful effects of bacteria, viruses or cancer. But in many diseases, there is too much inflammation; good examples are stroke, heart attack and auto immune diseases such as Crohn's Disease or lupus," he said.
'Rampant inflammation is harmful and leads to tissue damage, resulting in all kinds of side effects like pain, fatigue and regrettably also organ failure and death" Associate Professor Nold said.
Dr Claudia Nold said the study is universally applicable to all types of inflammation in patients of all ages, in conditions ranging from the common cold to serious life-threatening illnesses.
'IL-37 is able to override the body's own destructive responses to injury and disease, harnessing its fundamental mechanisms of action," she said.
To unravel the mechanistic details of IL-37's powerful effects, the research team used the Nobel Prize winning technique, Super Resolution Microscopy at Monash Micro Imaging and the Monash Institute of Pharmaceutical Sciences.
The advanced instruments allowed the scientists to see single molecules of IL-37 and its receptors, showing how IL-37 positions itself on the surface of target cells - something that had never been done before in previous studies in this field.
Dr Claudia Nold said the new findings make the vast potential of IL-37 accessible to drug development.
'IL-37 is extremely potent and effective in controlling inflammation, but to make it medically useful we needed to know how it works and what it does to cells," she said.
'Now we have deciphered these mechanisms we can pursue the medical potential of IL-37. This can be done by mimicking its effects when there is too much inflammation, or by blocking it when there is too little, like in cancer," Dr Nold said.
'It's important to note that this research is very early stage, but if we build on our discoveries and develop them further, it will be possible to deliver substantial and meaningful benefits to patients suffering from lots of diseases, be they acute or chronic, in a newborn baby or a centenarian" added Associate Professor Nold.
Question: Can you talk us through the protein that suppresses inflammation in the body?
Claudia Nold: Interleukin 37, abbreviated IL-37, is a member of the IL-1 family of cytokines, which has 11 members overall. Cytokines are small proteins that cells use to communicate with each other; and being members of a family means that these cytokines are built somewhat similarly.
An example for how cytokines work: Cell A will make IL-1 to alert cell B to a danger signal and get cell B in a mode of defense. If cell A makes IL-37 instead of IL-1, the message is the opposite, i.e. for cell B to be calm.
Question: What does this mean for the development of drugs to control inflammation?
Claudia Nold: There are a lot of cytokines like IL-1, which promote inflammation and are therefore called pro-inflammatory. Conversely, there are only quite few anti-inflammatory cytokines. And IL-37 stands out from this exclusive group, because it acts in a much broader fashion than most other known anti-inflammatory cytokines. The more we know about how IL-37 controls inflammation, the easier it is to make drugs that work like IL-37 - this is why discovering its receptor and signalling mechanisms is an important step forward.
Question: What's next in the study of IL-37?
Claudia Nold: There are very many ways how researchers all over the world can build on our discoveries. At our own laboratory, we are interested in diseases of newborn babies, and are currently exploring how IL-37 and its receptor can help prevent diseases that affect the babies' lungs, hearts or guts. Of course we will also continue to work on improving the understanding how the different cell types use IL-37 and its receptor for communication.
Question: Why do we all need to have inflammation to protect us?
Claudia Nold: Our immune system uses inflammation as a weapon to fight viruses or bacteria. If we did not have inflammation, the invading virus or bacterium would overrun the body and thereby rapidly kill it. We know this because there diseases in which a part of the immune system does not work; and the more parts of the immune system are affected, the faster and more severe are the consequences, including death.
Question: How long till we can begin testing these drugs?
Claudia Nold: This is not easy to predict, because the process of licensing a drug (which means obtaining permission from a government agency for doctors to prescribe a drug) has many components, each of which can hit hurdles. Drugs blocking of IL-1, which are in clinical use, took about 15 years from the time of discovery to reach patients. Today the process may be a bit quicker - we would estimate about 10 years.
Question: What diseases cause inflammation in the body?
Claudia Nold: Very, very many. In fact, there are not many diseases that are not accompanied by some form of inflammation. Besides viruses and bacteria, inflammation can be caused by mechanical insults such as a hammer on a finger, chemicals such as acid, by light as in a sunburn, and even by components of one's own body, as it happens in auto-immune diseases.
Question: How will these discoveries help monitor Lupus and other auto immune diseases, in the future?
Claudia Nold: Markers that allow monitoring how active a disease such as lupus is, or - even better - that predict how active it will be in a particular patient are called biomarkers. We are currently working on the question whether IL-37 could be a biomarker for lupus, but do not have an answer at this stage. Although it is possible that IL-37 may become a biomarker in a certain disease, the main focus of our research lies in harnessing the powerful activities of IL-37 to ultimately relieve the suffering of patients - even though we know that this goal is still a while away.
Interview by Brooke Hunter