Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease

Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical regulators of inflammatory disorders. The IL-33/ST2 axis is involved in the maintenance of intestinal homeostasis; on the basis of their role as pro- or anti-inflammatory mediators of first-line innate immunity, their expression is of great importance in regard to mucosal defenses. Mucosal immunity commonly presents an imbalance in inflammatory bowel disease (IBD). This review summarizes the main cellular and molecular aspects of IL-33 and ST2, mainly focusing on the current evidence of the pro- and anti-inflammatory effects of the IL-33/ST2 axis in the course of ulcerative colitis and Crohn's disease, as well as the molecular mechanisms underlying the association of IL-33/ST2 signaling in IBD pathogenesis. Although IL-33 modulates and impacts the development, course, and recurrence of the inflammatory response, the exact role of this molecule is elusive, and it seems to be associated with the subtype of the disease or the disease stage. Unraveling of IL-33/ST2-mediated mechanisms involved in IBD pathology shows great potential for clinical application as therapeutic targets in IBD treatment.

Automated summary

Interleukin-33 (IL-33) is a pleiotropic cytokine with both extracellular and nuclear functions, and its receptor ST2 plays a critical role in regulating inflammatory disorders. The IL-33/ST2 axis is involved in maintaining intestinal homeostasis and mucosal defenses. This review focuses on the pro- and anti-inflammatory effects of the IL-33/ST2 axis in ulcerative colitis and Crohn's disease, as well as the molecular mechanisms underlying its association with IBD pathogenesis. Understanding the IL-33/ST2-mediated mechanisms in IBD has potential for clinical applications as therapeutic targets.