Link between Genes that Cause Inflammatory Diseases May Lead to New Treatments

Researchers at Case Western Reserve University have discovered an association between two genes, one of which can cause Crohn’s Disease and other inflammatory diseases, showing a common pathophysiology that may lead to new treatments for Crohn’s and other gastrointestinal and inflammatory diseases.

According to study investigators, ITCH is a gene already known to regulate inflammation in the body that, when malfunctioning, can cause “widespread inflammatory diseases, including inflammatory bowel disease, gastritis, uncontrolled skin inflammation, and pulmonary pneumonitis.” NOD2 is a gene responsible for the majority of Crohn’s diagnoses that are genetic. Derek Abbott, MD, PhD, assistant professor of pathophysiology at Case’s School of Medicine, and his team of researchers discovered that the ITCH gene also has an influence on NOD2-induced inflammation.

In an abstract of the article that was published in Current Biology, Abbott and his team described the NOD2 signaling partner RIP2 as “directly K63-polyubiquitinated by ITCH.” In addition, the study results showed that “NOD2 can bind polyubiquitinated RIP2 and that whereas ITCH E3 ligase activity is required for optimal NOD2:RIP2-induced p38 and JNK activation, ITCH inhibits NOD2:RIP2-induced nuclear factor kappa B (NFB) activation.” This finding suggests “that ITCH helps regulate NOD2-dependent signal transduction pathways,” and, therefore, “may be involved in the pathogenesis of NOD2-mediated inflammatory disease.”

The next step for the researchers is to determine if current pharmacologic treatments “can be useful in this model of inflammatory disease,” which they will do by using “small molecule drug screening” to see what drugs potentially target the ITCH gene.

"This research is an excellent example of how scientific investments benefit the public with measurable gains. In this case, it led to unexpected insights and opened new fields of endeavor for pharmacological manipulation in this serious chronic disease," Abbott said. “This sort of study will help uncover the pathologic mechanism of disease and will ultimately lead to more rational and carefully measured treatment.”