Inhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation

• Several inhibitors of apoptosis (IAPs) mediate immune signaling through their ubiquitin ligase function.
• Additional IAPs control immunity through the regulation of the inflammasome.
• The IAPs contribute to immunity and immune disorders, such as inflammatory bowel disease (IBD).
• X-chromosome-linked IAP (XIAP) deficiency is now recognized as a monogenic cause of severe Crohn's-like disease.

The inhibitor of apoptosis (IAP) family members, notably cIAP1, cIAP2, and XIAP, are critical and universal regulators of tumor necrosis factor (TNF) mediated survival, inflammatory, and death signaling pathways. Furthermore, IAPs mediate the signaling of nucleotide-binding oligomerization domain (NOD)1/NOD2 and other intracellular NOD-like receptors in response to bacterial pathogens. These pathways are important to the pathogenesis and treatment of inflammatory bowel disease (IBD). Inactivating mutations in the X-chromosome-linked IAP (XIAP) gene causes an immunodeficiency syndrome, X-linked lymphoproliferative disease type 2 (XLP2), in which 20% of patients develop severe intestinal inflammation. In addition, 4% of males with early-onset IBD also have inactivating mutations in XIAP. Therefore, the IAPs play a greater role in gut homeostasis, immunity and IBD development than previously suspected, and may have therapeutic potential.