Published online Mar 21, 2022. doi: 10.3748/wjg.v28.i11.1139
Peer-review started: September 2, 2021
First decision: November 7, 2021
Revised: December 23, 2021
Accepted: February 12, 2022
Article in press: February 12, 2022
Published online: March 21, 2022
Gastric injury involving inflammation is one of the most common diseases of the digestive system worldwide and is associated with gastric ulcers and gastric cancer (GC). Matrix metallopeptidase-9 (MMP-9) plays an important role in the inflammation and progression of GC. Quercetin exhibits anti-inflammatory activities, but its effects and mechanism of action on human chronic gastritis remain unclear.
To assess whether tumor necrosis factor-α (TNF-α)-induced MMP-9 expression is involved in the anti-inflammatory effects of quercetin in normal human gastric mucosa epithelial cell line GES-1.
The objective of this study was to evaluate the anti- inflammatory effects and mechanisms of quercetin in GES-1 cells.
A GES-1 cell model was established to evaluate the anti-inflammatory effects of quercetin on TNF-α-induced overexpression of the proinflammatory MMP-9 protein. The cell counting Kit-8 assay was used to examine the effects of quercetin dose on GES-1 cell viability. Cell migration was measured using the Transwell assay. The expression of c-Src, phospho (p)-c-Src, p- extracellular-signal-regulated kinase (ERK) 1/2, ERK2, p-c-Fos, c-Fos, p-p65, and nuclear factor kappa B (NF-κB)/p65 and the effects of their inhibitors were examined using Western blot analysis and the measurement of luciferase activity. p65 expression was detected by immunofluorescence. MMP-9 mRNA and protein expression levels were determined by quantitative reverse transcription polymerase chain reaction (qRT–PCR) and gelatin zymography, respectively.
qRT–PCR and gelatin zymography showed that TNF-α induced MMP-9 mRNA and protein expression in a dose- and time-dependent manner. These effects were reduced by pretreatment of GES-1 cells with quercetin or TNF-α antagonist in a dose- and time-dependent manner. Quercetin decreased the TNF-α-induced phosphorylation of c-Src, ERK1/2, c-Fos, and p65 in a dose- and time-dependent manner. Quercetin, PP1, U0126, TSIIA, and a TNF-α antagonist reduced TNF-α-induced c-Fos phosphorylation and AP-1–Luc activity in a dose- and time-dependent manner. Pretreatment with quercetin, PP1, U0126, Bay 11-7082, or TNF-α antagonist reduced TNF-α-induced p65 phosphorylation and translocation and p65–Luc activity in a dose- and time-dependent manner. TNF-α significantly increased GES-1 cell migration, and this effect was reduced by pretreatment with quercetin and a TNF-α antagonist.
Quercetin significantly downregulates TNF-α-induced MMP-9 expression in GES-1 cells via the TNFR-c-Src–ERK1/2–c-Fos and NF-κB pathways.
We propose that quercetin potentially represents a new approach for reducing reliance on nonsteroidal anti-inflammatory drugs and an effective therapeutic agent for protecting gastric mucosal epithelial cells. Quercetin and quercetin-rich diets may exhibit potential as food supplements for the prevention of early pathological changes associated with gastric inflammation.