Research Identifies Key Molecular Actions of Autoimmune, Inflammatory Diseases

An immunomodulatory cytokine interacts with its receptors differently than other cytokines.

Scientists have recently discovered a crucial underlying mechanism involved with autoimmune and inflammatory conditions, including psoriasis, rheumatoid arthritis, and Crohn's disease.

According to the results of a study published by Immunity, the pro-inflammatory activity of the IL-23 cytokine is contingent on the structural activation by its receptor, IL-23R. The immunomodulatory cytokine IL-23 is involved with numerous inflammatory diseases.

New cases of psoriasis, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis have been skyrocketing over the past few decades, with many millions affected by each condition. The prevalence of these conditions made targeting IL-23 a focus of novel treatments, according to the authors.

Although IL-23 was discovered years ago, the structural and molecular mechanisms for its pro-inflammatory activity were unclear.

The study discusses how IL-23 interacts with its receptors. Cytokines typically activate its receptors, but the newly-discovered interaction appears to be the opposite, according to the study.

"We were surprised to find that both IL-23 and its receptor change drastically to create an intimate cytokine-receptor interface,” said lead researcher Savvas Savvides, PhD. “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 researchers analyzed integrative structural biology and combined strategies in order to describe protein structures in atomic detail for the first time, according to the study. They also evaluated biochemical, biophysical, cellular, and in vivo studies.

“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,” Dr Savvides said.

These findings may lead to novel therapies for autoimmune and inflammatory diseases that target the IL-23 receptor.

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

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