Scientists Determine Structure of Major Cytokine Involved in MS Inflammation

Scientists Determine Structure of Major Cytokine Involved in MS Inflammation

A global collaboration of researchers led by Belgium’s Flanders Institute for Biotechnology has determined the structure of the pro-inflammatory cytokine IL-23 and its receptor IL-23R, which could be potential targets for treating multiple sclerosis (MS) and other autoimmune diseases.

Their study, “Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1,” appeared in the journal Immunity.

IL-23 is a pro-inflammatory protein that plays a crucial role in inflammatory diseases including MS, rheumatoid arthritis, psoriasis and inflammatory bowel diseases. It functions by binding to IL-23R, which is embedded in the outer membrane of several types of immune cells. When IL-23 interacts with IL-23R at the cell surface, it triggers a series of chemical signals inside the cell that promote inflammation.

Although the regulatory functions and disease-related context of IL-23 is well-known, little information exists on the structure of this protein. For this reason, researchers set out to determine the structure of IL-23.

Researchers were able to map out the structure of IL-23 interacting with its receptor IL-23R based on biochemical and biophysical experiments. By determining the structure of the IL-23:IL-23R complex, scientists discovered that IL-23 binds IL-23R exclusively through the N-terminal immunoglobulin domain.

Interestingly, researchers discovered that upon binding of IL-23 to IL-23R, there was a partial restructuring of a subunit of IL-23 called the IL-23p19 subunit. Normally, cytokines tend to activate their receptors, but in this case, the opposite was also true.

The change in the structure of IL-23 allowed the IL-23R to restrain another subunit of IL-23 called the p40 subunit, which then allowed IL-23 to have a high-affinity interaction with another receptor, IL-12Rβ1. Activation of both IL-23R and IL-12Rβ1 led to pro-inflammatory signaling.

“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,” Savvas Savvides, lead author of the paper, said in a press release.

“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,” added Savvides.

These findings regarding the structure of IL-23 could represent the next treatment strategy for autoimmune diseases.

“Strategies addressing specifically the obligate IL-23:IL-23R binary complex or the functional hotspot…in IL-23p19 may offer additional avenues to address the broad spectrum of diseases linked to IL-23,” the study said.

Iqra holds a MSc in Cellular and Molecular Medicine from the University of Ottawa in Ottawa, Canada. She also holds a BSc in Life Sciences from Queen’s University in Kingston, Canada. Currently, she is completing a PhD in Laboratory Medicine and Pathobiology from the University of Toronto in Toronto, Canada. Her research has ranged from across various disease areas including Alzheimer’s disease, myelodysplastic syndrome, bleeding disorders and rare pediatric brain tumors.
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Iqra holds a MSc in Cellular and Molecular Medicine from the University of Ottawa in Ottawa, Canada. She also holds a BSc in Life Sciences from Queen’s University in Kingston, Canada. Currently, she is completing a PhD in Laboratory Medicine and Pathobiology from the University of Toronto in Toronto, Canada. Her research has ranged from across various disease areas including Alzheimer’s disease, myelodysplastic syndrome, bleeding disorders and rare pediatric brain tumors.
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3 comments

  1. charles says:

    I did not realize that the structure of il-23 was not already known and published. will this structure be available on ncbi?

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