Caspase-4 Activation in Association with Decreased Adenosine Deaminase Activity May Be a Factor for Gastric Ulcer

Abstract

Background/Aims: 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. Conclusion: 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.

Caspase-4: A Therapeutic Target for Peptic Ulcer Disease

“…1C). These findings confirm previously reported findings, suggesting that caspase-4 contributes to the inflammation and mucosal damage that occur during ulcer formation (15).…”

“…In this study, we report that caspase-4 is induced in peptic ulcer tissue, suggesting that noncanonical inflammasome activation and pyroptosis are processes participating in ulcer formation. Caspase-4 has previously been linked to decreased adenosine deaminase activity and implicated as a factor inducing gastric ulcers (15). Immune cells, such as macrophages, contribute to peptic ulcer formation through bacterial-induced inflammation (16).…”

Prognostic significance of mRNA expression of CASPs in gastric cancer

“…As for CASP4, this protein can be activated by declines in adenosine deaminase activity and could induce gastric epithelial cell apoptosis, promoting the formation of gastric ulcers; however, a small population of cells may undergo malignant transformation (32). The diagnostic value of adenosine deaminase is of less importance as its activity in GC did not significantly differ to that in normal mucosa (33).…”

GDF15 Protects Insulin-Producing Beta Cells against Pro-Inflammatory Cytokines and Metabolic Stress via Increased Deamination of Intracellular Adenosine

“…On the one hand, low extracellular concentrations of adenosine have been reported to increase beta-cell insulin release and proliferation via adenosine receptor activation [39]. On the other hand, high intracellular adenosine concentrations are known to promote cell death in different cells with decreased capacity for adenosine disposal (ADA-deficiency), such as immune cells in ADA-severe combined immune deficiency, neuronal cells, endothelial cells, epithelial cells, and cancer cells [40][41][42][43][44][45]. We have observed that high adenosine levels are toxic to beta cells [33], suggesting that the inherent capacity of beta cells to handle buildup of intracellular adenosine is low.…”