Glutamine Deprivation Causes Hydrogen Peroxide-induced Interleukin-8 Expression via Jak1/Stat3 Activation in Gastric Epithelial AGS Cells

Abstract

Background:The Janus kinase (Jak)/Signal transducers of activated transcription (Stat) pathway is an upstream signaling pathway for NF-κB activation in Helicobacter pylori-induced interleukin (IL)-8 production in gastric epithelial AGS cells. H. pylori activates NADPH oxidase and produces hydrogen peroxide, which activates Jak1/Stat3 in AGS cells. Therefore, hydrogen peroxide may be critical for IL-8 production via Jak/Stat activation in gastric epithelial cells. Glutamine is depleted during severe injury and stress and contributes to the formation of glutathione (GSH), which is involved in conversion of hydrogen peroxide into water as a cofactor for GSH peroxidase.Methods:We investigated whether glutamine deprivation induces hydrogen peroxide-mediated IL-8 production and whether hydrogen peroxide activates Jak1/Stat3 to induce IL-8 in AGS cells. Cells were cultured in the presence or absence of glutamine or hydrogen peroxide, with or without GSH or a the Jak/Stat specific inhibitor AG490.Results:Glutamine deprivation decreased GSH levels, but increased levels of hydrogen peroxide and IL-8, an effect that was inhibited by treatment with GSH. Hydrogen peroxide induced the activation of Jak1/Stat3 time-dependently. AG490 suppressed hydrogen peroxide- induced activation of Jak1/Stat3 and IL-8 expression in AGS cells, but did not affect levels of reactive oxygen species in AGS cells.Conclusions:In gastric epithelial AGS cells, glutamine deprivation increases hydrogen peroxide levels and IL-8 expression, which may be mediated by Jak1/Stat3 activation. Glutamine supplementation may be beneficial for preventing gastric inflammation by suppressing hydrogen peroxide-mediated Jak1/Stat3 activation and therefore, reducing IL-8 production. Scavenging hydrogen peroxide or targeting Jak1/Stat3 may also prevent oxidant-mediated gastric inflammation.

Effects of Helicobacter pylori on the glutathione-related pathway in gastric epithelial cells

“…The results from our study suggested the possibility that ROS production was higher in AGS cells infected with GC-derived H. pylori strains, because the decreased degree of GSH level and ratio of GSSG to GSH was greater in the GC-derived strains. A previous report showed that glutamine deficiency decreased the intracellular GSH level and increased the level of hydrogen peroxide, and moreover the GSH treatment cancelled these responses [24]. These results indicates that GSH worked to reduce ROS.…”

Comorbidity-associated glutamine deficiency is a predisposition to severe COVID-19

“…Ouwendijk et al suggested that regulated NETs formation may defend hosts against SARS-CoV-2 infection in asymptomatic or mild cases, but additional factors may lead to excessive NETs production and lung obstruction [ 25 ]. Comorbidity-associated glutamine deficiency may be one of the factors contributing to pathologic NETs production, as glutamine impaired the chemotactic migration of neutrophils to infection sites in an animal model [ 81 ], and glutamine deprivation induced the expression of IL-8 [ 82 , 83 ].…”

“…However, as mentioned above, we cannot expect the full restoration of SIRT1 activity by NAD + boosters, as SIRT1 expression is inhibited by SARS-CoV-2 infection. We should also keep in mind that glutamine has been reported as a STAT3 activator in some cancer cell lines [ 84 , 147 ], whereas others found that glutamine has STAT3 inhibiting activity [ 83 , 148 ].…”

Signaling pathways of oxidative stress response: the potential therapeutic targets in gastric cancer

“…Additionally, the production of hydrogen peroxide is encouraged, aggravating the effects of oxidative stress. However, GSH therapy is proved successful in alleviating the high ROS buildup ( 158 ). In conclusion, intestinalization in the gastric host cells is caused by low GSH levels.…”