CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease

Abstract

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.Crohn's disease ͉ ENTPD1

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

“…These findings are consistent with previous reports that ATP and adenosine exacerbates and protects against gut inflammation, respectively 37, 38, 39, 40. Mice deficient in NTPDases have more severe DSS‐induced colitis, and human ENTPD1 gene polymorphisms increased IBD susceptibility and also affected the homeostasis of the immune system 9, 36. Our results indicate that these protective roles of NTPDases are also likely to be mediated through modulating innate immune responses (e.g.…”

“…POM‐1 inhibits phosphohydrolysis of ATP by selectively targeting NTPDases, especially NTPDase1 and NTPDase3, both overexpressed in human inflamed intestinal mucosa (Figure 1b) 35. It has been reported that global deficiency of NTPDase1 or NTPDase3 resulted in exacerbation of DSS colitis 9, 36. DSS administration induced similar body weight loss in both control and POM‐1‐treated mice.…”

“…Furthermore, gene polymorphisms of ENTPD1 link to the human immune system under homeostatic and inflammatory conditions (e.g. IBD) 9, 10. These lines of evidence suggest that the control of purine metabolism is important in IBD.…”

Characterization of circulating microparticle-associated CD39 family ecto-nucleotidases in human plasma

“…To date, eight E-NTPDases have been identified in humans, where four of them, NTPDases 1, 2, 3, and 8 are found to be expressed on the plasma membrane [9,10]. NTPDase 1/CD39, the prototype of this family, plays a key role in mediating inflammation in disease entities such as acute lung injury [11], inflammatory bowel disease [12,13], diabetic nephropathy [14], and ischemic reperfusion injury [15]. Originally described as a B lymphocyte activation marker, CD39 is also expressed on endothelial cells and recently identified on circulating microparticles [16].…”

Eficácia terapêutica do Metotrexato na Artrite Reumatóide depende da expressão de células T reguladoras CD39+?

“…Estes marcadores estão funcionalmente ativos e possuem ação como indutores da adenosina pericelular (Deaglio et al, 2007). Assim, tendo em vista que um dos mecanismos de ação do MTX é manter os níveis de adenosina extracelular elevados e a importância da atividade das ectonucleotidases em gerar adenosina (Kobie et al, 2006;Friedman et al, 2009) -(direita) de indivíduos sadios (IS)( n = 5),pacientes R-MTX( n = 6) e UR-MTX( n = 6).Os gráficos representam a média ± SEM. *P < 0.05 comparado ao grupo IS.…”