Inflammatory bowel disease (IBD), a family of autoimmune diseases of the gut, has set researchers on a hunt to find therapeutic targets to stop microbes from launching the immune system into overdrive. Now, a new study by the University of Texas (UT) Southwestern reveals a set of interacting molecules in immune cells of the gut is responsible for preventing the inflammation seen in IBD. The findings suggest a new drug target for IBD and related conditions.
The new research is published in Cell Reports in a paper titled, “Pak2-mediated phosphorylation promotes RORγt ubiquitination and inhibits colonic inflammation.”
“Dysregulated interleukin-17 (IL-17) expression and its downstream signaling is strongly linked to inflammatory bowel diseases (IBDs),” wrote the researchers. “However, the molecular mechanisms by which the function of RORγt, the transcription factor of IL-17, is regulated remains elusive. By a mass spectrometry-based approach, we identify that Pak2, a serine (S)/threonine (T) kinase, directly associates with RORγt.”
“We discovered a fundamental mechanism that inhibits inflammation in the gut,” said Venuprasad Poojary, PhD, associate professor of internal medicine and immunology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. “Understanding these kinds of basic details about the immune system is essential for developing new strategies to treat inflammatory diseases.”
Researchers already knew that heightened levels of the immune molecule IL-17 are associated with the worst symptoms of IBD. However, drugs targeting IL-17 have been ineffective at treating IBD and pose the problem of impacting immune cells throughout the body.
In the new study, the researchers probed what other molecules interact in the inflammatory cells that produce IL-17 in the gut. The researchers dug up a protein called Pak2. In blocking the protein Pak2 in mice, the animals lost weight, had more colon inflammation, and showed other symptoms of IBD, including diarrhea and blood in their stools. In the presence of Pak2, however, the IBD-like inflammation eased.
The researchers observed that Pak2 binds to RORgt, a protein that activates the IL-17 gene. RORgt acts like an accelerator for inflammation by boosting levels of IL-17, while Pak2 acts like the brakes.
“We clearly showed that turning up this pathway can inhibit colon inflammation, and we think this pathway could be targeted to attenuate this inflammation as well,” explained Poojary.
“Although we studied this in the context of bowel diseases, we think this pathway is probably also applicable to other inflammatory diseases including multiple sclerosis and rheumatoid arthritis,” he concluded.