Scientists shed light on a key molecular mechanism of autoimmune and inflammatory diseases

January 17, 2018, VIB (the Flanders Institute for Biotechnology)

An international team of researchers led by prof. Savvas Savvides (VIB-UGent Center for Inflammation Research) has unraveled a crucial aspect of the molecular basis of autoimmune and inflammatory diseases such as psoriasis, rheumatoid arthritis and Crohn's disease. Focusing on the immunomodulatory cytokine IL-23 they discovered that its pro-inflammatory activity, which underlies a wide range of inflammatory diseases, critically depends on structural activation of the cytokine by its receptor, IL-23R. The results of the study are published in the leading journal Immunity.

The prevalence of psoriasis, , inflammatory bowel diseases, and multiple sclerosis, has been rapidly expanding over the last few decades. For instance, an estimated 125 million people worldwide are affected by psoriasis and another 100 million by rheumatoid arthritis, while the presence of inflammatory bowel diseases (Crohn's and ulcerative colitis) in ethnic populations and previously unaffected geographical regions is growing at alarming rates. The cytokine IL-23 – a specific type of immunomodulatory protein – plays a crucial role in these diseases. Consequently, IL-23 has become the focus of against such diseases.

Reversed roles: when receptor activates cytokine

Since the first description of IL-23 about a decade and a half ago, the structural and for the mechanisms underlying the pro-inflammatory activity of IL-23 remained unclear. Prof. Savvides and his team have now shed light on the unique way that IL-23 interacts with at least one of its receptors. In general, cytokines activate receptors. But surprisingly, in the current study, the opposite appeared to be true.

Prof. Savvas Savvides (VIB-UGent): "We were surprised to find that both IL-23 and its receptor change drastically to create an intimate cytokine-receptor interface. In this interface, the receptor uses a functional hotspot on IL-23, enabling it to recruit an essential co-receptor for pro-inflammatory signaling. The binding site of the co-receptor on IL-23 also emerged as an unexpected finding. What we have now discovered about the pro-inflammatory complex mediated by IL-23 appears to be a new paradigm in the field."

Continued combined expertise

The researchers relied on integrative structural biology, combining methods to describe protein structures in atomic detail with complementary biochemical, biophysical, cellular and in vivo studies.

Prof. Savvides (VIB-UGent): "These initial research milestones from our program on IL-23 will be the cornerstone for further research in our own labs and elsewhere. After all, many questions still remain unanswered. For instance: how does IL-23 bind with other possible co-? Furthermore, our insights are expected to fuel the development of new therapeutic strategies against IL-23."

Explore further: Cytokine controls immune cells that trigger inflammatory bowel disease, study finds

More information: Yehudi Bloch et al. Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1, Immunity (2017). DOI: 10.1016/j.immuni.2017.12.008

Related Stories

Cytokine controls immune cells that trigger inflammatory bowel disease, study finds

April 18, 2017
A certain cytokine, or small protein that helps cells communicate during immune responses, can control whether immune cells promote or suppress inflammatory bowel disease, a finding that could lead to new treatments, according ...

Researchers unravel viruses' strategies to dodge immune systems

November 7, 2016
As mammals evolve, so do mammalian viruses. In doing so, they develop creative and effective ways to counter and evade the antiviral responses of their mammal hosts' immune systems. Researching those mechanisms at the molecular ...

Autoimmune diseases increase cardiovascular and mortality risk

August 30, 2017
Researchers from the Hospital del Mar Medical Research Institute (IMIM) and IDIAP Jordi Gol have just published an article showing that autoimmune diseases significantly increase cardiovascular risk as well as overall mortality. ...

Research opens up new treatment route for inflammatory rheumatism

August 23, 2016
Enthesitis, inflammation of tendons where they attach to the bone, is a common medical problem which underlies various forms of inflammatory rheumatism. Although around 1% of the population is affected, the mechanisms driving ...

Recommended for you

Quintupling inhaler medication may not prevent asthma attacks in children

March 19, 2018
Children with mild to moderate asthma do not benefit from a common practice of increasing their inhaled steroids at the first signs of an asthma exacerbation, according to clinical trial results published in The New England ...

How allergens trigger asthma attacks

March 19, 2018
A team of Inserm and CNRS researchers from the Institute of Pharmacology and Structural Biology have identified a protein that acts like a sensor detecting allergens in the respiratory tract that are responsible for asthma ...

Single steroid-bronchodilator treatment for control and rescue improves persistent asthma

March 19, 2018
When it comes to treating teens and adults with persistent asthma, using a single corticosteroid and long-acting bronchodilator treatment for both daily asthma control and for rescue relief during sudden asthma attacks is ...

Obesity and health problems: New research on a safeguard mechanism

March 16, 2018
Obesity and its negative impacts on health - including metabolic syndrome, type-2 diabetes mellitus and cardiovascular complications - are a global pandemic (Taubes, 2009). The worldwide incidence of obesity has more than ...

Immune system 'double agent' could be new ally in cancer fight

March 16, 2018
St. Jude Children's Research Hospital scientists have discovered that an enzyme called TAK1 functions like a "double agent" in the innate immune response, serving as an unexpected regulator of inflammation and cell death. ...

Artificial sweetener Splenda could intensify symptoms in those with Crohn's disease

March 15, 2018
In a study that has implications for humans with inflammatory diseases, researchers from Case Western Reserve University School of Medicine and colleagues have found that, given over a six-week period, the artificial sweetener ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.