Trends in Molecular Medicine
ReviewInhibitors of apoptosis (IAPs) regulate intestinal immunity and inflammatory bowel disease (IBD) inflammation
Section snippets
Inflammatory bowel disease
Inflammatory bowel disease (IBD; see Glossary) comprises a variety of chronic disorders affecting the gastrointestinal tract, of which Crohn's disease (CD) and ulcerative colitis (UC) are the two most frequent entities 1, 2. Both disorders results in chronic and relapsing inflammation, and they have an increasing incidence and prevalence globally [3]. Extrapolation from available data suggests that in the United States and Canada more than 800 000 individuals have UC and 650 000 have CD [3].
The IAP family: more than apoptosis
The viral IAPs were originally identified based on their ability to suppress Baculovirus-induced insect cell death. The subsequent identification of cellular insect and mammalian IAP genes also revealed roles for the IAPs in blocking apoptosis induced by a multitude of death triggers. Some IAPs, such as XIAP, are potent and direct inhibitors of initiator and effectors caspases (the proteases responsible for cell death execution), while other IAPs, such as cellular IAP1 (cIAP1) and cIAP2, can
Innate immune signaling pathways regulated by the IAPs
A number of receptors involved in immune responses have been shown to signal through the IAP ubiquitin ligases (cIAP1, cIAP2, XIAP), including the TNF-receptor superfamily member (e.g., TNF-R1 and CD40) pathways, as well as the Toll-like receptors (TLR) and NOD receptors. Furthermore, the induction of IL-1 through the inflammasome is mediated by NAIP.
Evidence for IAP involvement in IBD
The IAPs are crucial for signaling responses to various innate immune stimuli, including those thought to be important in the triggering and development of IBD. Their ability to inhibit apoptosis and to mediate the expression of proinflammatory cytokines through the NF-κB pathways, as well as the MAPK pathways, is suggestive of a key role in IBD. In addition, both CD and UC are characterized by an increased expression of immune cells as well as proinflammatory cytokines in the intestine 76, 77.
New drug targets in IBD
The ability of IAPs to inhibit apoptosis in immune cells and to control innate immune signaling makes them an interesting therapeutic target. By blocking IAP expression or function with small molecules to ultimately decrease the number and function of immune cells at the site of inflammation, the expression of proinflammatory cytokines in inflamed tissues may be reduced and may control the severity of IBD.
The natural endogenous inhibitor of the IAPs, the mitochondrial protein SMAC, is released
Concluding remarks and future perspectives
The evidence that IAPs are important regulators of pathways involved in the gut immune system, and IBD in particular, is growing and warrants further investigation. The preclinical testing of small molecule IAP antagonists in valid models of IBD also demands consideration to ascertain the therapeutic utility of cIAP1/2 depletion and its possible effects on TNF-α production and target tissue sensitivity. The data presented indicates, however, that IAPs play an important role in various immune
Acknowledgments
J.B.S. was supported by a grant from the Danish Council for Independent Research, Health and Disease.
Glossary
- Apoptosis
- A form of programmed cell death. This death is mediated by caspases, which ultimately leads to elimination of the cell without releasing harmful inflammatory substances into the surrounding area.
- Cell death-inducing caspases
- family of proteases, including initiator caspases, for example, caspase 8 (CASP8) and CASP9, which cleave and activate effector caspases, such as CASP3. This proteolytic cascade leads to the characteristic morphological and biochemical hallmarks of apoptosis, and
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