Implication of interferon-γ in TFF1 silencing during H. pylori chronic Infection

FÁTIMA MARIA MENTUCCI; VOLI, ANTONIA; ELETTO, DANIELA; PORTA, AMALIA; TOSCO, ALESSANDRA

Roma

Congreso; 17th SIBBM Seminar ?Frontiers in Molecular Biology. The RNA World 3.0?; 2022

Helicobacter pylori is responsible for one of the most common worldwide infections. Thegastric mucosa acts as the first line of defense against H. pylori infection, triggering differentprocesses to eliminate the bacterium and prevent it from remaining in the gastrointestinaltract. H. pylori induced mucosal inflammatory response includes the activation andinfiltration of macrophages and dendritic cells with the consequent secretion of cytokines,such as IL-1β, IL-6, TNF-α and IFN-γ. Even so, this response often fails to eradicate thepathogen. Unless the infection is treated, it persists lifelong and develops into chronicgastritis and, in a subset of individuals, lesions can silently progress to cancer. The gastricmucosa also secretes several protective factors, including the Trefoil Factor 1 (TFF1), whichinteracts with the bacterium and retains it in the mucus layer preventing its migrationtowards the gastric epithelium. It was observed that TFF1 expression is affected by thissustained inflammatory response. Indeed, it is stimulated by the initial exposure to thepathogen but gradually silenced during continuous inflammation and cytokines’ release.Since little is known about the TFF1 downregulation during Helicobacter chronic infection,we investigated the molecular mechanisms leading to its silencing. Our data suggest thatamong the cytokines overexpressed during H. pylori infection, IFN-γ is involved in TFF1down-regulation in gastric cells. This transcriptional repression seems to occur through aspecific transcription factor, C/EBPβ, which is able to bind three different sites on the TFF1promoter, particularly under IFN-γ stimulation. Remarkably, chemical inhibition of DNAmethylation reverts C/EBPβ binding to the TFF1 promoter and restores TFF1 expression.