Patients with Inflammatory Bowel Disease (IBD) suffer exaggerated gut inflammation that often leads to an imbalance in the types of microbes found in their intestines. Thus IBD patients often display a loss of typically beneficial bacteria and an overgrowth of potentially dangerous bacteria. In healthy individuals, such responses are typically prevented by the expression of SIGIRR, a protein expressed by the epithelial cells that line the gut. SIGIRR plays a key role in suppressing responses that drive inflammation and kill bacteria. We previously showed that loss of SIGIRR by these epithelial cells dramatically increases their inflammatory and bacterial killing abilities. Moreover, SIGIRR plays such a key role in the health of the human gut that its loss leads to severe and often lethal forms of necrotizing enterocolitis while in mice, loss of SIGIRR causes exaggerated gut inflammation, the death of good bacteria and susceptibility to the overgrowth of dangerous bacteria. While we currently do not have a way to promote the beneficial actions of SIGIRR in the gut, recently, interleukin (IL)-37, a newly recognized anti-inflammatory cytokine, has been shown to use SIGIRR to inhibit inflammatory responses in human cells. In this project, we plan to test the ability of IL-37 to signal through SIGIRR to control inflammatory and bacterial killing responses in epithelial cells, limit experimental IBD in mice, and promote normal gut microbe balance. Ultimately, my studies will explore the potential for IL-37 to act as a new therapeutic for patients with IBD.