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Published on: January 5, 2017
CD73 Blockade Aggravate Dextran-Sodium-Sulfate-Induced Colitis via Down Regulating Inosine
Lan Yang1, Xi Wang1, Fang Lin1
1Department of Clinical Laboratory, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710038, People's Republic of China.
Background:
CD73, a pivotal enzyme in the purinergic signaling cascade, modulates the concentrations of adenosine and inosine. These metabolites are involved in immune responses and inflammatory processes. This study aims to investigate the function of CD73 in the pathogenesis of inflammatory bowel disease (IBD) and explore the potential mechanism.
Methods:
Dextran-Sodium-Sulfate (DSS)-induced colitis mice models were established by orally administering 3% DSS. CD73 was blocked by intraperitoneal injection of Adenosine 5'- (α, β-methylene) diphosphate (APCP). Inosine was supplemented by intraperitoneal injection. Hematoxylin-eosin (H&E), PAS and Alcian blue staining were used to evaluate the inflammation infiltration and colon damage. Serum IL-6 levels were detected by ELISA assay. High-performance liquid chromatography-mass spectrometry (LC-MS) was used to investigate the level of inosine.
Results:
Blockade of CD73 by APCP aggravated disease severity in DSS-induced colitis mice models, characterized by increased weight loss, colon shortening and pathological damage, increased disease activity and IL-6 production. Blocking CD73 impairs intestinal barrier function and integrity by reducing the expression of tight junction proteins (claudin-1, occludin and ZO-1), both in colon tissues and intestinal epithelial cell-MODE-K. In addition, APCP increased oxidative stress in colon tissue and MODE-K (increased MDA level, decreased SOD and GSH activities). Moreover, blocking CD73 reduced inosine levels in vivo and in vitro. We found that inosine treatment significantly ameliorated DSS-induced colitis in mice, as demonstrated by decreased weight loss, less colon shortening and histological injury, reduced disease activity and IL-6 production. Notably, the effects of inosine on MODE-K cells were opposite to those of APCP, including the effects on the expression of oxidative stress molecules and tight junction proteins.
Conclusion:
This study indicates that CD73 exerts a protective effect in the progress of DSS-induced colitis. Inosine supplementation might be a potential therapeutic strategy for colitis.
Insights
CD73 plays a protective role in inflammatory bowel disease (IBD). Blocking CD73 worsens colitis, while inosine supplementation ameliorates symptoms, suggesting it as a potential therapeutic strategy for IBD.
Area of Science:
- Immunology
- Gastroenterology
- Biochemistry
Background:
- CD73 is an enzyme crucial for purinergic signaling, regulating adenosine and inosine levels.
- These metabolites influence immune and inflammatory responses.
- The role of CD73 in inflammatory bowel disease (IBD) pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the function of CD73 in the pathogenesis of inflammatory bowel disease (IBD).
- To explore the underlying mechanisms of CD73's action in IBD.
- To evaluate inosine as a potential therapeutic agent for colitis.
Main Methods:
- Dextran-Sodium-Sulfate (DSS)-induced colitis mouse models were used.
- CD73 was blocked using Adenosine 5'- (α, β-methylene) diphosphate (APCP); inosine was supplemented.
- Histological analysis (H&E, PAS, Alcian blue), ELISA for IL-6, and LC-MS for inosine levels were performed.
Main Results:
- Blocking CD73 aggravated DSS-induced colitis, increasing weight loss, colon damage, and IL-6 production.
- CD73 blockade impaired intestinal barrier function by reducing tight junction proteins and increased oxidative stress.
- Inosine treatment significantly ameliorated colitis symptoms and counteracted the effects of CD73 blockade.
Conclusions:
- CD73 exhibits a protective effect in DSS-induced colitis.
- Inosine supplementation demonstrates therapeutic potential for colitis treatment.
- Modulating CD73 and inosine levels offers a promising strategy for managing IBD.
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