Interleukin-6 signaling regulates small intestinal crypt homeostasis

Gut homeostasis is a tightly regulated process requiring finely-tuned complex interactions between different cell types, growth factors or cytokines and their receptors. Previous work has implicated a role for interleukin (IL-6) and mucosal immune cells in intestinal regeneration following injury and in promoting inflammation and cancer. We hypothesized that IL-6 signaling could also modulate crypt homeostasis. Using mouse in vitro crypt organoid and in vivo models this study first demonstrated that exogenous IL-6 promoted crypt organoid proliferation and increased stem cell number through pSTAT3 activation in Paneth cells. Immunolabelling studies showed that the IL-6 receptor was restricted to the basal membrane of Paneth cells both in vitro and in vivo and that the crypt epithelium also expressed IL-6. Either a blocking antibody to the IL-6 receptor or a neutralising antibody to IL-6 significantly reduced in vitro basal crypt organoid proliferation and budding, and in vivo significantly reduced the number of nuclei and the number of Lgr5EGFP positive stem cells per crypt compared to IgG treated mice, with the number of Paneth cells per crypt also significantly reduced. Functional studies demonstrated that IL-6-induced in vitro crypt organoid proliferation and crypt budding was abrogated by the Wnt inhibitor IWP2. This work demonstrates that autocrine IL-6 signaling in the gut epithelium regulates crypt homeostasis through the Paneth cell and the Wnt signaling pathway.