Inhibition of the dephosphorylation of eukaryotic initiation factor 2α ameliorates murine experimental colitis.

Abstract

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.

• Authors: Takashi Okazaki, Akiyoshi Nishio, Masahiro Takeo, Yutaku Sakaguchi, Toshiro Fukui, Kazushige Uchida, Kazuichi Okazaki
• Journal: Digestion (Digestion) Vol. 90 Issue 3 Pg. 167-78 ( 2014) ISSN: 1421-9867 [Electronic] Switzerland
• PMID: 25339182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cinnamates
• DNA-Binding Proteins
• Elf2 protein, mouse
• Endoplasmic Reticulum Chaperone BiP
• Eukaryotic Initiation Factor-2
• HSP70 Heat-Shock Proteins
• Heat-Shock Proteins
• Interleukins
• RNA, Messenger
• Regulatory Factor X Transcription Factors
• Transcription Factors
• Tumor Necrosis Factor-alpha
• salubrinal
• Dextran Sulfate
• Peroxidase
• PERK kinase
• eIF-2 Kinase
• Thiourea

Topics

• Animals
• Cinnamates (administration & dosage)
• Colitis (chemically induced, drug therapy, metabolism, pathology)
• Colon (drug effects, metabolism, pathology)
• DNA-Binding Proteins (antagonists & inhibitors, drug effects, genetics, metabolism)
• Dextran Sulfate
• Disease Models, Animal
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Eukaryotic Initiation Factor-2 (drug effects)
• HSP70 Heat-Shock Proteins (metabolism)
• Heat-Shock Proteins (metabolism)
• Injections, Intraperitoneal
• Interleukins (genetics, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Peroxidase (metabolism)
• RNA, Messenger (metabolism)
• Regulatory Factor X Transcription Factors
• Thiourea (administration & dosage, analogs & derivatives)
• Transcription Factors (antagonists & inhibitors, drug effects, genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Weight Loss (drug effects)
• eIF-2 Kinase (drug effects, genetics, metabolism)