The role of TNFAIP3 in intestinal homeostasis and autoimmunity

Failure to control inflammation significantly contributes to metabolic disease. Inflammation plays a central, critical role in many metabolic inflammatory diseases. In these diseases, somewhere in the pathological process, inflammation is not regulated. Thus, a central question regarding inflammation is what contributes to lack of control and loss of the homeostatic point? Inducers of inflammation are the factors that lead to the initiation or the propagation of the inflammatory state; however, just as necessary are the negative regulators of inflammation that allow for the return to homeostasis. Thus, diminished capacity to negatively regulate inflammation alone may be sufficient to cause inflammatory disorders. It is therefore important to understand the mechanisms that control the negative regulation of inflammation. One critical negative regulator of inflammation is tumor necrosis factor alpha-induced protein 3 (TNFAIP3, also known as A20).;TNFAIP3 is a unique cytoplasmic, dual action ubiquitin-editing protein. TNFAIP3 can inhibit inflammatory responses and regulate pathological activation of nuclear factor-kappa B, c-Jun N-terminal kinase and apoptosis in hematopoietic cells and fibroblasts, however its function in other cell types has been less well characterized. Mice deficient for TNFAIP3 exhibit are hypersensitive to tumor necrosis factor and lipopolysaccharide, develop severe multi-organ inflammation and die prematurely, indicating a potential role for TNFAIP3 in homeostatic control mechanisms. Studies at the genetic, functional, and physiological level have demonstrated associations between alterations in TNFAIP3 and numerous inflammatory immunopathologies; however, it unknown to what extent they are differentially regulated by TNFAIP3.;We show that TNFAIP3 is a central regulator of homeostasis and plays a key role in the negative regulation of inflammation and potentially the prevention of autoimmune diseases such as systemic lupus erythematosus and IBD. This linkage is most likely a result of the multiple roles TNFAIP3 plays in different cell types. In addition to TNFAIP3's established anti-inflammatory and anti-apoptotic roles, we show that it plays a role in intestinal epithelial cell tight junction dynamics. TNFAIP3's regulation of these important pathways is cell specific and context dependent and thus the role of TNFAIP3 in different inflammatory diseases likely reflects the distinct roles of TNFAIP3 in different cells and contexts.