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

doi:10.1016/j.molmed.2014.09.006

Trends in Molecular Medicine

Volume 20, Issue 11, November 2014, Pages 652-665

https://doi.org/10.1016/j.molmed.2014.09.006 Get rights and content

Highlights

•
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.

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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Trends in Molecular Medicine

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

Highlights

Section snippets

Inflammatory bowel disease

The IAP family: more than apoptosis

Innate immune signaling pathways regulated by the IAPs

Evidence for IAP involvement in IBD

New drug targets in IBD

Concluding remarks and future perspectives

Acknowledgments

Glossary

Lancet

Lancet

Immunol. Lett.

J. Crohns Colitis

Gastroenterology

Lancet

Immunity

Mol. Cell

J. Biol. Chem.

Mol. Cell

Mol. Cell

Mol. Cell

Cell

Mol. Cell

Trends Immunol.

J. Biol. Chem.

Mol. Cell

Mol. Cell

Clin. Chim. Acta

Immunity

J. Biol. Chem.

Am. J. Pathol.

Mol. Cell

Cell Host Microbe

Immunity

Immunity

Biochem. Biophys. Res. Commun.

Blood

Mol. Cell

Blood

Mol. Cells

Lancet

Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review

Gastroenterology

Intestinal homeostasis and its breakdown in inflammatory bowel disease

Nature

Cytokine-based therapies for Crohn's disease – new paradigms

N. Engl. J. Med.

Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study

Inflamm. Bowel Dis.

Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Nature

New IBD genetics: common pathways with other diseases

Gut

Inflammatory bowel disease

N. Engl. J. Med.

NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation

Nat. Med.

A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Nature

Crohn's disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2

Gut

XIAP mediates NOD signaling via interaction with RIP2

Proc. Natl. Acad. Sci. U.S.A.

XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs

EMBO J.

Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation

Proc. Natl. Acad. Sci. U.S.A.

Tumor necrosis factor inhibitors for inflammatory bowel disease

N. Engl. J. Med.

Which biological agents are most appropriate for ulcerative colitis?

Ann. Intern. Med.

Inflammatory pathways of importance for management of inflammatory bowel disease

World J. Gastroenterol.

Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival

Mol. Cell. Biol.

Upregulation of cIAP2 in regenerating colonocytes in ulcerative colitis

Virchows Arch.

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