Inflammatory Bowel Disease Activated by Inhibitors of Apoptosis

Inhibitors of apoptosis (IAP), or programmed cell death, are critical and universal regulators of tumor necrosis factor (TNF), according to a review of the current literature published in Trends in Molecular Medicine.

Researchers from the Children’s Hospital of Eastern Ontario Research Institute in Ottawa, Canada studied the existing literature surrounding the role of the IAP family, which includes cIAP1, cIAP2, and X-linked IAP (XIAP).

“We were motivated to write this review based on 2 significant discoveries of late, for which most physicians and specialists, including gastroenterologists, may not be aware of, and which may impact upon the future practice of medicine,” Eric LaCasse, PhD, corresponding of the author of the study, explained to Internal Medicine World Report in an email.

Currently, the existing literature suggests the role of XIAP can lead to a primary immunodeficiency in individuals and can present a severe form of colitis or resemble Crohn’s disease (CD). Secondly, the literature proposes the inflammatory cytokine TNFa shows beneficial results in the treatment of inflammatory bowel disease (IBD).

The investigators noted the IAPs contain an ubiquitin-associated (UBA) domain. This allows the formation of target proteins to aid IAP signaling. It can lead to cell survival, cell migration, and recruitment. They can also induce cytokine and chemokine production.

Additionally, the researchers learned that XIAP may lead to IBD — the 2 X-linked disorders, X-linked immune disorder (XLP2) and X-linked lymphoproliferative disease (XLP1), both share recurring, potentially fatal bouts of hemophagocytic lymphohystiocytosis (LHL) in response to the Epstein-Barr virus and other infections. XLP2 disorders can lead to severe intestinal bleeding, though XLP1 can sometimes enhance symptoms for the XIAP-deficient individuals.

The researchers found there is a surprising amount of literature that contributes to the support of a role for the IAPs in gut immunity and disease — including the fact that multiple IAPs could supply gut microbiome interaction and biology and the development of inflammatory disease.

IBD in XIAP deficient individuals were typically male patients, as noted in the literature, though female heterozygous carriers have also been identified as carriers for CD-like diseases. The mutated allele comes from an abnormal skewing of the X-chromosome inactivation in the subjects’ leukocytes.

“We expect that diagnostic and treatment guidelines will emerge as to the management of these individuals, and suggest when stem cell transplants are recommended,” LaCasse told IMWR what physicians can take away from these findings. “The potential therapeutic use of Smac mimetics in IBD is highly debatable, and will require much more preclinical investigation to warrant any clinical studies of their efficacy and toxicity for IBD.”

IAPs were discovered by the same research hospital nearly 2 decades ago, and since then, IAPs have been shown to be cancer-causing genes, regulators of cell division, and suppressors of cell death, controllers of cell signaling and motility, and mediators of the innate community.

In the future, the researchers hope their findings can fuel further research, specifically looking into controlling innate immune IAP signaling.

“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 authors conclude.