IBD can reduce quality of life, so finding new treatments for it is vital.
Researchers at Sanford Burnham Prebys (SBP) Medical Discovery Institute in La Jolla, CA, and Technion-Israel Institute of Technology in Haifa have identified a role for a protein called RNF5, which is abundant in cells that line the gut.
They found that RNF5 controls the activity of S100A8, a protein already known to be a promoter of inflammation.
By manipulating the RNF5 gene in mice, the scientists found that RNF5 keeps S100A8 stable in cells of the gut lining, and that its absence unleashes the pro-inflammatory power of S100A8.
The researchers report their new findings in a study paper that features in the journal Cell Reports.
Inflammatory bowel disease (IBD) is the general term for a collection of disorders that persistently inflame the gastrointestinal tract, or gut.
There are two main kinds of IBD: Crohn's disease, which can inflame any part of the gut between the mouth and the anus; and ulcerative colitis, which mainly affects the colon.
An 'urgent need' for new IBD treatments
IBD can cause symptoms that, in turn, cause discomfort, pain, and distress. These include: diarrhea, constipation, rectal bleeding, abdominal pain and cramp, and a sudden and urgent need to go to the bathroom.
According to the Centers for Disease Control and Prevention (CDC), around 3 million adults in the United States report having received a diagnosis of IBD.
Current treatments do not work in all cases, and they can also become less effective over time.
"People with IBD are in urgent need of new treatments," says senior investigator Ze'ev A. Ronai, a professor in the NCI-designated Cancer Center at SBP.
Despite the fact that for some time it has been known that inflammatory proteins are involved in IBD, the underlying driving mechanism has remained a mystery.
The recent findings have helped solve a big part of that mystery and should now lead to more consistent targeted treatments.
RNF5 moderates pro-inflammatory S100A8
Prof. Ronai and team noticed that mice lacking the RNF5 gene had little gut inflammation. They did, however, develop acute colitis when exposed to dextran sodium sulfate, which is a compound that induces inflammation. This test suggested that RNF5 might have a key role in halting inflammation.
The investigators then searched for pro-inflammatory proteins that RNF5 might keep in check and decided that the most likely candidate was S100A8, which had already been tied to several inflammatory conditions and is also used as a biomarker for aiding IBD diagnosis.
The RNF5-deleted mice also had higher levels of S100A8 in their blood and in the cells lining their guts. Giving the mice S100A8-neutralizing antibodies also stopped acute colitis symptoms, confirming the protein's role in driving inflammation.
"Our findings," says Prof. Ronai, "indicate that RNF5 is the lock that keeps a key inflammatory protein under control."
Breaking the lock is like opening "Pandora's box," he adds, and the result is that "S100A8 is released to cause inflammation."
Results confirmed in human samples
In a final set of experiments, the researchers confirmed their findings in human gut samples. They tested tissue samples that had been taken from the intestines of 19 people with ulcerative colitis and compared the results with tests done on healthy tissue.
The tests revealed that low RNF5 and high S100A8 levels correlated with disease severity, which reflected the findings from the RNF5-deleted mice.
The results are consistent with the idea that IBD might respond to drugs that either deactivate S100A8 or regulate RNF5, Prof. Ronai suggests.
"RNF5 also appears to be a potential predictor of disease severity, and could be used as a diagnostic marker," he concludes.
"Once we identified S100A8 as a protein regulated by RNF5 in the cells that line the gut, we realized we may have identified an important player in IBD."
Prof. Ze'ev A. Ronai