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Inhibition of the dephosphorylation of eukaryotic initiation factor 2α ameliorates murine experimental colitis
Background/Aims:
Endoplasmic reticulum (ER) stress in the intestine is closely associated with the development of inflammatory bowel disease (IBD). However, the role of the protein kinase RNA-like ER kinase in this disease is not fully known. We studied whether an inhibitor of the dephosphorylation of eukaryotic initiation factor 2α, salubrinal, improves murine experimental colitis through the amelioration of ER stress.
Methods:
Colitis was induced by the administration of 3% dextran sulfate sodium (DSS) for 5 days. Mice were injected salubrinal intraperitoneally from the commencement of DSS treatment and were sacrificed on day 10. The severity of colitis was evaluated histologically using a scoring system.Myeloperoxidase activity and the expression of proinflammatory cytokine genes in the colon were analyzed. The expression levels of ER stress-related proteins were evaluated by Western blotting.
Results:
The administration of salubrinal significantly attenuated body weight loss and improved colitis, as assessed histologically. The elevation of myeloperoxidase activity and the expression of proinflammatory cytokine genes were suppressed in salubrinal-treated mice. The expression of glucose-regulated protein 78, activating translation factor 4, and heat-shock protein 70 was elevated in mice treated with salubrinal.
Conclusion:
The amelioration of ER stress may be a therapeutic target for the treatment of IBD.
Insights
Salubrinal, an endoplasmic reticulum (ER) stress inhibitor, improved experimental colitis in mice. This suggests that targeting ER stress may be a viable therapeutic strategy for inflammatory bowel disease (IBD).
Area of Science:
- Gastroenterology
- Molecular Biology
- Immunology
Background:
- Endoplasmic reticulum (ER) stress is linked to inflammatory bowel disease (IBD).
- The specific role of protein kinase RNA-like ER kinase in IBD remains unclear.
- Investigating ER stress modulation as a potential therapeutic avenue for IBD is crucial.
Purpose of the Study:
- To determine if salubrinal, an inhibitor of eukaryotic initiation factor 2α dephosphorylation, can ameliorate experimental colitis in mice.
- To assess the impact of salubrinal on ER stress markers in the context of colitis.
Main Methods:
- Experimental colitis was induced in mice using dextran sulfate sodium (DSS).
- Salubrinal was administered intraperitoneally to mice during DSS treatment.
- Colitis severity, myeloperoxidase activity, proinflammatory cytokine gene expression, and ER stress-related proteins were analyzed.
Main Results:
- Salubrinal treatment significantly reduced body weight loss and improved histological scores of colitis.
- Myeloperoxidase activity and proinflammatory cytokine gene expression were suppressed in salubrinal-treated mice.
- Expression of ER stress markers (GRP78, eIF4G, HSP70) was elevated with salubrinal administration.
Conclusions:
- Amelioration of ER stress shows promise as a therapeutic strategy for inflammatory bowel disease.
- Salubrinal effectively reduced inflammation and ER stress in a murine model of colitis.
- Targeting ER stress pathways could offer new treatment options for IBD patients.
