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The Structure of Major Cytokine Found to be Involved in MS Inflammation

January 23, 2018

Researchers around the globe being let by Belgium’s Flanders Institute for Biotechnology have determined the structure of the pro-inflammatory cytokine IL-23 and its receptor IL-23R, making them potential targets for treating autoimmune diseases like multiple sclerosis (MS).

The study is called, “Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.”
Since IL-23 is a pro-inflammatory protein, it plays a crucial role in inflammatory diseases including rheumatoid arthritis, psoriasis as well as inflammatory bowel diseases. It functions by binding to IL-23R, which is actually embedded in the outer membrane of several immune cells. It eventually promotes inflammation when interacting with IL-23R at the cell surface.

While this information is already known to most, researchers decided to look deeper into the structure of IL-23. They were able to dig deeper into this complex discovery based on biochemical and biophysical experiments. They found that IL-23 binds IL-23R exclusively through the N-terminal immunoglobulin domain.

Upon binding of IL-23 to IL-23R, there was a partial restructuring of a subunit of IL-23 called the IL-23p19 subunit. Cytokines normally activate their receptors, although the opposite was found to be true in this case. The change in structure of IL-23 is what allowed the IL-23R to restrain another subunit of IL-23 called the p40 subunit. This then allowed IL-23 to have a high-affinity interaction with another receptor IL-12Rβ1. The activation of both IL-23R and IL-12Rβ1 is what led to pro-inflammatory signaling.

Lead author of the paper, Savvas Savvides, said in a press release, “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,” Savvides continued.
These discoveries could represent the next treatment strategy for autoimmune diseases.

https://multiplesclerosisnewstoday.com/2018/01/22/scientists-shed-light-on-a-key-molecular-mechanism-of-autoimmune-and-inflammatory-diseases/