Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling

The latent transcription factor Stat3 is activated by gp130, the common receptor for the interleukin (IL)-6 cytokine family andother growth factor and cytokine receptors. Ligand-induced dimerization of gp130 leads to activation of the Stat1, Stat3 andShp2-Ras-Erk signaling pathways. Here we assess genetically the contribution of exaggerated Stat3 activation to the phenotypeof gp130Y757F/Y757F mice, in which a knock-in mutation disrupts the negative feedback mechanism on gp130-dependent Statsignaling. Compared to gp130Y757F/Y757F mice, reduced Stat3 activation in gp130Y757F/Y757F Stat3+/− mice increased theirlifespan, prevented splenomegaly, normalized exaggerated hepatic acute-phase response and lymphocyte trafficking, andsuppressed the growth of spontaneously arising gastric adenomas in young mice. These lesions share histological features ofgastric polyps in aging mice with monoallelic null mutations in Smad4, which encodes the common transducer for transforminggrowth factor (TGF)-β signaling. Indeed, hyperactivation of Stat3 desensitizes gp130Y757F/Y757F cells to the cytostatic effect ofTGF-β through transcriptional induction of inhibitory Smad7, thereby providing a novel link for cross-talk between Stat and Smadsignaling in gastric homeostasis.