Constitutive STAT3 serine phosphorylation promotes Helicobacter-mediated gastric disease.

Gastric cancer is associated with chronic inflammation (gastritis) triggered by infection with the Helicobacter pylori (H. pylori) bacterium. Elevated tyrosine phosphorylation (pY) of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and is aligned to nuclear transcriptional activity. By contrast, the transcriptional role of STAT3 serine phosphorylation (pS), which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling pS-STAT3-deficient Stat3^SA/SA mice with chronic H. felis infection, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells, and expression analyses of inflammatory genes, revealed that chronic gastritis was markedly suppressed in infected Stat3^SA/SA mice compared to wild-type (WT) mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3^SA/SA (compared to WT) mice, which was associated with reduced proliferative potential of infected Stat3^SA/SA gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3^SA/SA mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumourigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than its effect on mitochondrial and metabolic gene networks. In gastric mucosa of mice and gastritis patients, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.