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

Abstract

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.

Immune-Modulating Effects of Low-Carbohydrate Ketogenic Foods in Healthy Canines

“…These studies indicate that IL-8 is an important contributor to IBD, and strategies to reduce their expression may be beneficial. IL-33 is another cytokine, and in some cases acts as a transcription factor, that is implicated in IBD in humans [ 90 ]. However, the role of IL-33 in the pathology of IBD is not clear as it can exert a proinflammatory effect and, in some instances, an anti-inflammatory effect as well [ 91 , 92 ].…”

The role of complex interactions between the intestinal flora and host in regulating intestinal homeostasis and inflammatory bowel disease

“…IL-33 was therefore suggested to act by inhibiting the development of IBD ( Malik et al, 2016 ). This relationship illustrates the limitations of studies on particular inflammatory factor signaling pathways, and suggests the need to evaluation of “when” and “how” the IL-33/ST2 signaling when exploring novel IL-33-targeting biological agents in the therapeutic armamentarium against IBD in the future ( Aggeletopoulou et al, 2022 ).…”

A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis

“…The interaction between IL-33 and its ST2 receptor plays a crucial role in regulating inflammatory disorders. The IL-33/ST2 axis is a key player in maintaining intestinal homeostasis and is integral to the balance between pro-and anti-inflammatory responses in mucosal defenses [193]. IL-33 exhibits dual functionality, existing in two forms: full-length IL-33 (flIL-33) as an intranuclear gene regulator and mature IL-33 (mIL-33) functioning as an extracellular cytokine released from damaged or necrotic cells.…”