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 4

FOLH1–/– mice are protected against dextran sodium sulfate–induced colitis.

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FOLH1–/– mice are protected against dextran sodium sulfate–induced coli...
FOLH1–/– and WT mice were given dextran sodium sulfate (DSS) in their drinking water for 7 days, and disease activity index (DAI) was monitored daily. Data are shown as mean ± SEM (n = 14 mice/group). (A) FOLH1–/– mice showed significantly reduced DAI compared with WT mice (**P < 0.01, ***P < 0.001, 2-way ANOVA). (B) FOLH1–/– mice showed significantly longer colons compared with WT, suggesting reduced inflammation (n = 5–14 mice per group) (***P < 0.001, 2-tailed t test). (C) Histological evaluation confirmed that FOLH1–/– mice exhibited markedly reduced disease in response to DSS (n = 5 per group). WT mice exhibited thickening of the colon wall, including mucosa and muscular layers, as well as massive leukocyte infiltration, loss of crypts, and diminishing goblet cells, while the FOLH1–/– mice showed relatively minor changes, with clearly defined crypts and visible goblet cells, as well as drastically reduced number of inflammatory cell infiltration. Original magnification, ×100. M, mucosal layer; SM, submucosal; ML, muscular layer.