NEW YORK (GenomeWeb) – Through a global transcriptome analysis, researchers have found that patients with more severe inflammatory bowel disease (IBD) also have increased activity of blood coagulation-related genes like PAI-1.
About 3 million adults in the US have reported being diagnosed with IBD, according to the Centers for Disease Control and Prevention, but only a small number respond to treatment.
Washington University School of Medicine's Thaddeus Stappenbeck and his colleagues analyzed global gene expression patterns within colon biopsies from ulcerative colitis and Crohn's disease patients — both types of IBD — and controls to find that patients had increased activity of genes involved in blood coagulation. As they reported in Science Translational Medicine today, the researchers noted that the patients also had increased levels of the PAI-1 protein, which, in mice, leads to colon inflammation and could be targeted by a small molecule.
"There's a lot of interest in novel therapeutic approaches for IBD because inhibiting inflammatory molecules doesn't work for all patients," Stappenbeck said in a statement. "We found a unique target that's not an inflammatory molecule, and yet blocking it reduces inflammation and signs of disease, at least in mice. If further research bears out our findings, we think this target could be helpful to a greater number of patients."
He and his team examined global gene expression within colon biopsies obtained from individuals with ulcerative colitis and Crohn's disease as well as from controls. More than 1,770 genes were dysregulated between the biopsies from IBD patients and non-IBD controls. Using a number of analytical tools, the researchers found that this set of genes was enriched for ones involved in coagulation or hemostasis. This, the researchers noted, could also account for the increased risk of blood clots among IBD patients.
They further refined their targets through network analysis and biological pathway and cell-type enrichment analyses to focus on the gene SERPINE1, as it is linked to both inflammation and the intestinal epithelium.
They found that expression of SERPINE1, which encodes the protein PAI-1, is increased in IBD colon biopsies taken at active or inflamed sites, as compared to samples from uninvolved regions, or from those in remission or who are unaffected. The researchers further identified a set of 380 genes whose expression correlated with SERPINE1, which they noted was enriched for genes involved in cytokine or chemokine inflammation and the extracellular matrix. In a mouse model of colitis, the researchers found that PAI-1 expression exacerbated disease symptoms.
In particular, they found that increased PAI-1 levels were more common among patients with severe disease as well as among patients who were resistant to anti–tumor necrosis factor (anti-TNF) treatment.
Through additional mouse studies, the researchers reported that PAI-1 promotes inflammation through its interaction with tissue plasminogen activator (tPA) protein. PAI-1 binds and inhibits tPA, which typically protects against colitis and mucosal damage within the intestines. But by binding tPA, the researchers found that PAI-1 blocks its ability to activate the transforming growth factor-beta (TGF-β), which the researchers noted has a known anti-inflammatory role in IBD and anti-proliferative effect on epithelial cells.
But, inhibiting PAI-1 could mitigate its inflammatory influence, the researchers reported. They used the small molecule MDI-2268 to block PAI-1 in mice. This reduced both mucosal damage and inflammation. In particular, the researchers noted that it rescued TGF-β activity and increased the ratio of active to total tPA in both plasma and colon tissue.
This suggested to the researchers that increased PAI-1 levels may lead to more aggressive disease, but also indicated that it could be a therapeutic target.
"What's most exciting here is that SERPINE-1 and its protein seems to be most highly expressed in people with the most severe disease and those who don't respond to immunosuppressive biologics," Stappenbeck said.