Suppression of expression of endoplasmic reticulum chaperones by Helicobacter pylori and its role in exacerbation of non-steroidal anti-inflammatory drug-induced gastric lesions.

Abstract

Both the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, and infection with Helicobacter pylori are major causes of gastric ulcers. Although some clinical studies suggest that infection with H. pylori increases the risk of developing NSAID-induced gastric lesions, the molecular mechanism governing this effect is unknown. We recently found that in cultured gastric cells, expression of endoplasmic reticulum (ER) chaperones (such as 150-kDa oxygen-regulated protein (ORP150) and glucose-regulated protein 78 (GRP78)) is induced by NSAIDs and confers protection against NSAID-induced apoptosis, which is important in the development of NSAID-induced gastric lesions. In this study we have found that co-culture of gastric cells with H. pylori suppresses the expression of ER chaperones. This suppression was regulated at the level of transcription and accompanied by a reduction in the level of activating transcription factor 6 (ATF6), one of the transcription factors for ER chaperone genes. In vivo, inoculation of mice with H. pylori suppressed the expression of ER chaperones at gastric mucosa both with and without administration of indomethacin. Inoculation with H. pylori also stimulated formation of indomethacin-induced gastric lesions and mucosal cell death. In addition, we found that heterozygous ORP150-deficient mice are sensitive to the development of indomethacin-induced gastric lesions and mucosal cell death. The results of this study suggest that H. pylori exacerbates NSAID-induced gastric lesions through suppression of expression of ER chaperones, which stimulates NSAID-induced mucosal cell death.

• Authors: Takushi Namba, Tatsuya Hoshino, Shintaro Suemasu, Mika Takarada-Iemata, Osamu Hori, Naomi Nakagata, Akinori Yanaka, Tohru Mizushima
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 48 Pg. 37302-13 (Nov 26 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20861013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Endoplasmic Reticulum Chaperone BiP
• HSP70 Heat-Shock Proteins
• HSPA5 protein, human
• Heat-Shock Proteins
• Hspa5 protein, mouse
• Molecular Chaperones
• Proteins
• oxygen-regulated proteins
• Indomethacin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (adverse effects)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Endoplasmic Reticulum (drug effects, genetics, metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Gastric Mucosa (drug effects, metabolism, microbiology, pathology)
• HSP70 Heat-Shock Proteins
• Heat-Shock Proteins (genetics, metabolism)
• Helicobacter Infections (genetics, metabolism, microbiology, pathology)
• Helicobacter pylori (physiology)
• Humans
• Indomethacin (adverse effects)
• Mice
• Mice, Knockout
• Molecular Chaperones (genetics, metabolism)
• Proteins (genetics, metabolism)