IL-1RT1 signaling antagonizes IL-11 induced STAT3 dependent cardiac and antral stomach tumor development through myeloid cell enrichment

Abstract

IL-1 is key driver of gastric tumorigenesis and is a downstream target of IL-11 signaling. Recently, IL-1 cytokines, particularly IL-1β, have been flagged as therapeutic targets for gastric cancer treatment. Here, we assess the requirement for IL-1 signaling in gastric tumorigenesis. gp130^757FF xIL-1RT1^–/^– mice were generated to determine the pathological consequence of ablated IL-1 signaling in the IL-11 dependent gp130^757FF mouse model of gastric tumorigenesis. Gastric lesions in gp130^757FF xIL-1RT1^–/^– mice were increased in incidence and size compared to gp130^757FF mice. Proximal gastric lesions originated from the cardiac region and were associated with elevated STAT3 activation, loss of specialized gastric cells and a modulated immune response including increased expression of TNF-α and MDSC associated genes. Administration of IL-11 to IL-1RT1^–/^– mice showed similar changes to gp130^757FF xIL-1RT1^–/^– mice. Spleens from IL-11 treated wildtype mice showed an enrichment of MDSC and gp130^757FF xIL-1RT1^–/^– mice had increased MDSCs in the stomach compared to gp130^757FF mice. Furthermore, crossing TNF-α^–/^– to gp130^757FF mice resulted in reduced lesion size. We conclude that IL-1 signaling antagonizes IL-11/STAT3 mediated pathology and the genetic deletion of IL-1RT1 results in increased tumor burden. We provide evidence that a likely mechanism is due to IL-11/STAT3 dependent enrichment of MDSCs.