Key Interleukins in Inflammatory Bowel Disease-A Review of Recent Studies

Abstract

Inflammatory bowel disease (IBD) is an immune disorder of the gastrointestinal tract with a complex aetiopathogenesis, whose development is influenced by many factors. The prevalence of IBD is increasing worldwide, in both industrialized and developing countries, making IBD a global health problem that seriously affects quality of life. In 2019, there were approximately 4.9 million cases of IBD worldwide. Such a large number of patients entails significant healthcare costs. In the treatment of patients with IBD, the current therapeutic target is mucosal healing, as intestinal inflammation often persists despite resolution of abdominal symptoms. Treatment strategies include amino salicylates, corticosteroids, immunosuppressants, and biologic therapies that focus on reducing intestinal mucosal inflammation, inducing and prolonging disease remission, and treating complications. The American College of Gastroenterology (ACG) guidelines also indicate that nutritional therapies may be considered in addition to other therapies. However, current therapeutic approaches are not fully effective and are associated with various limitations, such as drug resistance, variable efficacy, and side effects. As the chronic inflammation that accompanies IBD is characterized by infiltration of a variety of immune cells and increased expression of a number of pro-inflammatory cytokines, including IL-6, TNF-α, IL-12, IL-23 and IFN-γ, new therapeutic approaches are mainly targeting immune pathways. Interleukins are one of the molecular targets in IBD therapy. Interleukins and related cytokines serve as a means of communication for innate and adaptive immune cells, as well as nonimmune cells and tissues. These cytokines play an important role in the pathogenesis and course of IBD, making them promising targets for current and future therapies. In our work, we review scientific studies published between January 2022 and November 2024 describing the most important interleukins involved in the pathogenesis of IBD. Some of the papers present new data on the precise role that individual interleukins play in IBD. New clinical data have also been provided, particularly on blocking interleukin 23 and interleukin 1beta. In addition, several new approaches to the use of different interleukins in the treatment of IBD have been described in recent years.

Keywords: Crohn’s disease; inflammatory bowel disease; interleukin 10; interleukin 12; interleukin 17; interleukin 1β; interleukin 22; interleukin 23; interleukin 33; interleukin 6; interleukins; recent studies; ulcerative colitis.

Figure 1

The figure shows a cross section of a healthy bowel and a bowel affected by inflammatory bowel disease (IBD). The figure shows the differences in intestinal barrier structure, epithelial permeability, and immune cell activity.

Figure 2

IL-6 signaling occurs through two mechanisms: classical and trans. Classical signaling occurs via the membrane-bound IL-6R receptor and affects a limited number of cells that express the membrane-anchored form of IL-6R and gp130. Trans signaling is mediated by the soluble IL-6R receptor and affects cells that do not have membrane expression of IL-6R but do have gp130. By affecting all gp130-expressing cells, the mechanism is almost universal. Trans-signaling is thought to be the reason for the chronic inflammatory effect of IL-6.

Figure 3

The figure shows the NOX2-ROS-Lyn-SHP-1 pathway in monocytes through which TNFα inhibits STAT3 phosphorylation induced by IL-10. 1. TNF-α, acting through its receptors (TNF-R), phosphorylates the p47PHOX subunit of NOX2, leading to activation of the complex. 2. The activated NOX2 complex generates reactive oxygen species (ROS) from NADPH and molecular oxygen (O₂). 3. ROS activate Lyn kinase, oxidizing thiol groups of cysteines (-SH) to sulfenic groups (-SOH). 4. Activated Lyn kinase phosphorylates tyrosine phosphatase (SHP-1), which is crucial for its activity. 5. IL-10 acts on monocytes by activating a receptor composed of two subunits IL-10R1 and IL-10R2. Activation of this receptor leads to STAT3 phosphorylation. 6. Active SHP-1de-phosphorylates STAT3, leading to its inactivation. 7. Disruption of STAT3 phosphorylation leads to inhibition of SOCS3 (suppressor of cytokine signaling 3) expression, which is the major anti-inflammatory gene activated by STAT3.

Figure 4

The figure shows IL-12, which induces polarization of naive T cells towards Th1 cells, which then produce pro-inflammatory cytokines such as IFN-γ and TNFα. IL-23, on the other hand, is involved in the differentiation of naive T lymphocytes towards Th17 lymphocytes, which increase the secretion of other inflammatory cytokines such as IL-17 and IL-22. IL-12 and IL-23 are heterodimeric cytokines that share the IL-12p40 subunit. The IL-12p35 subunit binds to the IL-12Rβ2 receptor, while IL-23p19 binds to the IL-23R receptor, which induces structural changes that facilitate the association of the IL-12p40 subunit with the IL-12Rβ1 chain. The monoclonal antibody ustekinumab binds to the IL-12p40 subunit, blocking both IL-12 and IL-23 cytokine signaling, while antibodies such as mirikizumab, risankizumab, brazikumab, and guselkumab target the IL-23p19 subunit.