CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease
Open accessAbstract
CD39/ENTPD1 hydrolyzes proinflammatory nucleotides to generate adenosine. As purinergic mediators have been implicated in intestinal inflammation, we hypothesized that CD39 might protect against inflammatory bowel disease. We studied these possibilities in a mouse model of colitis using mice with global CD39 deletion. We then tested whether human genetic polymorphisms in the CD39 gene might influence susceptibility to Crohn's disease. We induced colitis in mice using Dextran Sodium Sulfate (DSS). Readouts included disease activity scores, histological evidence of injury, and markers of inflammatory activity. We used HapMap cell lines to find SNPs that tag for CD39 expression, and then compared the frequency of subjects with high vs. low CD39-expression genotypes in a case-control cohort for Crohn's disease. Mice null for CD39 were highly susceptible to DSS injury, with heterozygote mice showing an intermediate phenotype compared to wild type (WT). We identified a common SNP that tags CD39 mRNA expression levels in man. The SNP tagging low levels of CD39 expression was associated with increased susceptibility to Crohn's disease in a case-control cohort comprised of 1,748 Crohn's patients and 2,936 controls ( P = 0.005–0.0006). Our data indicate that CD39 deficiency exacerbates murine colitis and suggest that CD39 polymorphisms are associated with inflammatory bowel disease in humans.
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Individuals with reduced ability to transcribe CD39 due to a promoter polymorphism have better responses to TIV and VZV vaccination.
“Consistent with these in vitro observations, individuals with reduced ability to transcribe CD39 due to a promoter polymorphism (Friedman et al., 2009) have better responses to TIV as well as VZV vaccination”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Friedman et al., 2009
In humans, polymorphisms of ENTPD1 are associated with IBD, and P2X7 expression is increased in the intestinal epithelium and lamina propria of IBD patients.
“In humans, polymorphisms of ENTPD1 were shown to be associated with IBD, and expression of P2X7 was increased in the intestinal epithelium and lamina propria of IBD patients (Friedman et al., 2009; Neves et al., 2014).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Friedman et al., 2009
Entpd1−/− mice, which cannot remove extracellular ATP through this mechanism, were highly susceptible to experimental colitis.
“Entpd1−/− mice, which cannot remove extracellular ATP through this mechanism, where highly susceptible to experimental colitis (Friedman et al., 2009).”
From Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System (2017) · cites this paper as Friedman et al., 2009
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Purinergic Signaling in Gut Inflammation: The Role of Connexins and Pannexins
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- Authors
- Friedman, D. J., Künzli, B. M., A-Rahim, Y. I., Sevigny, J., Berberat, P. O., Enjyoji, K., Csizmadia, E., Friess, H., & Robson, S. C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- University of Hawaiʻi at Mānoa (US)
- Transplantation Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard University, 330 Brookline Avenue, Boston, MA 02215;
- Technical University of Munich (DE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09-29
- Volume
- 106
- Issue
- 39
- Pages
- 16788-16793
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2757811
- OpenAlex
- W2163178183
- Cited by
- 284
- References
- 40
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 12 · 2023: 14 · 2022: 23 · 2021: 15 · 2020: 25 · 2019: 23 · 2018: 15 · 2017: 20 · 2016: 18 · 2015: 20 · 2014: 20 · 2013: 15 · 2012: 21
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Wellcome Trust
- National Institutes of Health (5p01hl076540-10)
- National Heart, Lung, and Blood Institute (HL-57307, HL63972, HL 076540, R01HL094400, P01 HL-076540, R01HL057307, R01HL063972)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK076868)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- CD39, adenosine, purinergic signaling, inflammatory bowel disease, Crohn's disease, colitis, DSS-induced colitis, genetic polymorphism, single nucleotide polymorphisms, genetic susceptibility, nucleotide hydrolysis
- MeSH terms
- Animals, Apyrase, Colitis, Crohn Disease, Disease Models, Animal, Genotype, Humans, Mice, Inbred C57BL, Polymorphism, Genetic, RNA, Messenger, Inflammatory Bowel Diseases, Antigens, CD, Sequence Deletion, Genetic Predisposition to Disease, Mice
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