FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities
Rana Rais, … , Xuhang Li, Barbara S. Slusher
Rana Rais, … , Xuhang Li, Barbara S. Slusher
Published August 4, 2016
Citation Information: JCI Insight. 2016;1(12):e88634. https://doi.org/10.1172/jci.insight.88634.
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Research Article Gastroenterology

FOLH1/GCPII is elevated in IBD patients, and its inhibition ameliorates murine IBD abnormalities

Abstract

Recent gene-profiling analyses showed significant upregulation of the folate hydrolase (FOLH1) gene in the affected intestinal mucosa of patients with inflammatory bowel disease (IBD). The FOLH1 gene encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase II (GCPII). To establish that the previously reported increased gene expression was functional, we quantified the glutamate carboxypeptidase enzymatic activity in 31 surgical specimens and report a robust 2.8- to 41-fold increase in enzymatic activity in the affected intestinal mucosa of IBD patients compared with an uninvolved area in the same patients or intestinal mucosa from healthy controls. Using a human-to-mouse approach, we next showed a similar enzymatic increase in two well-validated IBD murine models and evaluated the therapeutic effect of the potent FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) (IC50 = 300 pM). In the dextran sodium sulfate (DSS) colitis model, 2-PMPA inhibited the GCPII activity in the colonic mucosa by over 90% and substantially reduced the disease activity. The significance of the target was confirmed in FOLH1–/– mice who exhibited resistance to DSS treatment. In the murine IL-10–/– model of spontaneous colitis, daily 2-PMPA treatment also significantly reduced both macroscopic and microscopic disease severity. These results provide the first evidence of FOLH1/GCPII enzymatic inhibition as a therapeutic option for IBD.

Authors

Rana Rais, Weiwei Jiang, Huihong Zhai, Krystyna M. Wozniak, Marigo Stathis, Kristen R. Hollinger, Ajit G. Thomas, Camilo Rojas, James J. Vornov, Michael Marohn, Xuhang Li, Barbara S. Slusher

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Figure 1

Elevation of FOLH1/glutamate carboxypeptidase II activity in the diseased intestinal mucosa of patients with IBD.

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Elevation of FOLH1/glutamate carboxypeptidase II activity in the disease...
FOLH1/glutamate carboxypeptidase II (FOLH1/GCPII) enzymatic activity was measured in involved (inflamed with active disease) and uninvolved (macroscopically normal) mucosal specimens from IBD patients or from non-IBD controls. (A) Significant enhancement of GCPII activity was observed in diseased mucosal specimens taken from Crohn’s disease (CD) and ulcerative colitis (UC) patients when compared with specimens from normal healthy controls in both colon and ileum. Data are shown as mean ± SEM (n = 31 samples) (*P < 0.05, **P < 0.01, 2-tailed t test). (B) Within the same IBD patient, a robust increase in enzymatic activity was observed in the diseased intestinal mucosa specimens when compared with that in an uninvolved region from the same patient. Data are presented as individual specimens (n = 19). The Arabic numbers refer to different patients. The pound sign indicates that an uninvolved normal region from this patient was not available.