Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1-/- macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.
Animals, Bone Marrow Cells, Bone Marrow Transplantation, Colitis, Colon, Disease Models, Animal, Female, Helicobacter Infections, Helicobacter hepaticus, Humans, Inflammatory Bowel Diseases, Interleukin-12, Interleukin-23, Macrophages, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Primary Cell Culture, Protein Kinases, Radiation Chimera, Th1 Cells