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Getting to the Heart of Inflammation

Many babies born prematurely suffer from different kinds of inflammation.

Many babies born prematurely suffer, sometimes fatally, from different kinds of inflammation.

By Julia Veitch

Pre-term babies with bronchopulmonary disease are providing insights into inflammatory responses behind diseases as diverse as migraine, arthritis and diabetes.

Inflammation is a hot topic in medical research. As more is understood about various chronic disease processes, it has become evident that acute and chronic inflammation can be damaging. The hunt is on for a means to silence any excessive inflammatory process and provide a therapy for diseases caused by inflammation.

Inflammation is the crucial first step to fighting infection and promoting healing. An inflammatory response usually takes place any time a foreign body invades our body, which might be a physical object such as a splinter, or a bug of some sort, such as bacteria or viruses. The body begins to attack the foreign object using inflammation to destroy or contain it. In a healthy person, once the inflammation has run its course and destroyed or disabled whatever is causing the response, it goes away.

Inflammatory activity is regulated by immediate feedback so that it doesn’t get out of hand. This is analogous to the various negative feedback cycles in our body that maintain temperature, blood glucose and sodium at optimum levels.

However, while most of us have a robust, healthy and stable immune system, things do go wrong. Diseases caused by not enough inflammation are very rare, usually with a hereditary component. The converse, disease caused by too much inflammation, is common.

Indeed, there is a vast array of problems caused by excessive or disregulated inflammation. Millions of people worldwide suffer from diseases caused by too much inflammation, such as the auto-immune diseases lupus and rheumatoid arthritis and many other conditions such as septic shock, myalgia, migraine, gout, arthritis, cancer and diabetes. An excess of fat cells causes an inflammatory response, increasing the risk of heart attack and diabetes in overweight people.

Inflammation has been implicated in two of the western world’s major cardiovascular diseases, atherosclerosis and coronary artery disease. Immune cells dominate early atherosclerotic lesions; their effector molecules accelerate progression of the lesions; and continuous inflammation can bring on acute coronary syndromes.

Over the past few decades it has been realised that the process of inflammation is virtually the same in different diseases, with the result that a better understanding of inflammation could lead to better treatments for many diseases.

Drs Claudia and Marcel Nold are a husband-and-wife team based at The Ritchie Centre in the Monash Institute of Medical Research. They are immunologists whose research focuses on one particular protein, a cytokine, in inflammatory responses.

Claudia is a lab-based researcher and Marcel is both a researcher and a pediatric clinician working with newborn babies at the Monash Medical Centre. Many of these babies are born prematurely and suffer, sometimes fatally, from different kinds of inflammation.

In particular Marcel works with babies suffering bronchopulmonary dysplasia (BPD), one of the major causes of mortality and long-term morbidity in preterm neonates. More than half of preterm babies with a birthweight of 501–750 g and more than one-third of those with a birthweight of 751–1000 g who survive the neonatal period will develop BPD. The treatment for these babies is limited to supportive measures as no target therapy exists for BPD.

The Nolds’ particular translational research study will be with this group of patients. However, their basic research could be applicable for all kinds of disorders caused by inflammation.

“If inflammation is the root cause of so many diseases, then we need to stop inflammation before it causes damage,” Marcel Nold says. “But how do we accomplish that?

“While there are existing effective anti-inflammatory medications, such as non-steroidal anti-inflammatory drugs, glucocorticoids or sirolimus-coated stents used after angioplasty, they can have serious adverse effects with prolonged use. This is why the body’s own naturally occurring blockers of the immune response are highly sought after. Not only do such blockers have the potential to serve as therapeutic alternatives to existing therapies, they could be both more effective but still have a favourable profile of adverse effects.”

As soon as it became apparent that cytokines serve as master regulators of the immune system and its biological processes about 30 years ago, these molecules have enjoyed the limelight of biomedical research. In particular, anti-inflammatory cytokines have received considerable attention as they can potentially replace anti-inflammatory drugs that have known adverse effects.

Cytokines are small proteins produced by many cells in the body. Those that are produced by leukocytes (white blood cells) are called interleukins (IL). They are intercellular and intracellular communication agents that signal cells to behave in particular ways, for example pro-inflammatory or anti-inflammatory.

After the identification of the “fever factor” in 1977, just two decades passed until blockade of interleukin 1 (IL-1) was introduced into clinical medicine. Although the role of the classical IL-1 family members in the immune response is now firmly established, much less is known about the seven newer members of the IL-1 family.

The Nolds became interested in one particular IL-1 molecule that is now known as IL-37 after the recent Nature Immunology publication they published with Prof Charles Dinarello of the University of Colorado. They established and elaborated the anti-inflammatory function of IL-37, and are planning to investigate its mechanisms.

Claudia Nold says that IL-37 “is a fundamental inhibitor of immune response. One way how it works is by acting on dendritic cells. Dendritic cells are the central coordinators of the immune system, collecting information and acting on it. They produce core stimulatory responses, and IL-37 silences their activity.

“But we don’t quite know the mechanism of how IL-37 affects downstream functions, such as which receptor is involved. Ongoing research has already given us some idea of how this might work. Although it’s difficult to work out what goes on inside a cell, we have understood in part that another intracellular messenger, Smad3, cooperates with IL-37.

“We recently revealed IL-37’s protective activity in a mouse model of myocardial infarction – heart attack – as well as in a model of ischaemia and reperfusion in the murine heart. Based on the pilot data we generated in the USA, we are continuing here in Australia to explore how IL-37 protects against myocardial infarction. We are also aiming to identify its yet-unknown receptor.”

It is noteworthy that, unlike the majority of anti-inflammatory cytokines, IL-37 is not a specific antagonist of one particular inflammatory trigger, but confers protection against a wide spectrum of insults. Since the number of pro-inflammatory cytokines vastly exceeds the number of anti-inflammatory cytokines, biological redundancy is considerably smaller in the anti-inflammatory group. Therefore, the effect of modulating the activity of any individual anti-inflammatory cytokine is likely to be greater than changing the activity of any pro-inflammatory cytokine.

This fact has been recognised by biomedical researchers and pharmaceutical companies that invest large amounts of time and money into anti-inflammatory mediators. The potential value of identifying a new modulator of the immune response is highlighted by its possible role in a wide spectrum of diseases.

The Nolds are careful to point out that it is easy to make claims for potential therapies. “It is very early stages for IL-37,” Marcel Nold says. “One has to be aware that it is a long process to translate findings from basic research to clinical application. We can see that this is a promising beginning, but we know it’s a long, complex and expensive process. There are many good ideas, few of which come to fruition.

“However, we’re fortunate to have received National Health and Medical Research Council funding to continue our research and hope to be able to make a substantial contribution to treating inflammatory diseases more effectively and thereby improve the quality of life of many people.”

Julia Veitch is Communications Manager with Monash University’s Central Clinical School.