Caspase-4 activation in association with decreased adenosine deaminase activity may be a factor for gastric ulcer.
OBJECTIVE
Adenosine deaminase (ADA)-deficient disease, a severe combined immunodeficiency, is most commonly associated with gastrointestinal disorders such as ulcer. The present study investigated the role of ADA in the pathogenesis of gastric ulcer.


METHODS
ADA activity was measured in a variety of organs and tissues from rats and in human gastric biopsy samples from patients who underwent gastrofiberscope. An MTT assay and TUNEL staining were carried out, and activity of caspase-3 and -4 was enzymatically measured in MKN45 human gastric cancer cells. In the Western blot analysis, caspase-4 activation was identified in gastric biopsy samples.


RESULTS
In rat organs and tissues, the epithelium of the gastrointestine exhibited higher ADA activity. The ADA inhibitor EHNA reduced cell viability, increased TUNEL-positive cells, and activated caspase-3 and -4 in MKN45 cells. For gastric biopsy samples, much lower ADA activity was found in gastric ulcer tissues, with a tendency of caspase-4 activation.


CONCLUSIONS
A decline in ADA activity and the ensuing increase in intracellular adenosine concentrations for the stomach could induce gastric epithelial cell apoptosis by activating caspase-4 and the effector caspase-3. This may represent a fresh pathogenetical pathway for gastric ulcer relevant to ADA activity and caspase-4 activation.
Yaguchi
Takahiro
T
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
Saito
Masaru
M
Yasuda
Yoshiyuki
Y
Nishizaki
Tomoyuki
T
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism; D000243:Adenosine Deaminase / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005753:Gastric Mucosa / Q000201:enzymology; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D051381:Rats; D013270:Stomach / Q000201:enzymology*; D013276:Stomach Ulcer / Q000209:etiology*
D004791:Enzyme Inhibitors; C010192:9-(2-hydroxy-3-nonyl)adenine; C093516:CASP4 protein, human; D053148:Caspase 3; D053471:Caspases, Initiator; D000243:Adenosine Deaminase; D000225:Adenine; D000241:Adenosine