Recently, interleukins have been considered as potential therapeutic targets in inflammatory bowel disease (IBD). Similarly, Crohn’s disease (CD) and ulcerative colitis (UC) are thought to be triggered by an exaggerated immune response against the intestinal flora. CD exhibits the features of an exaggerated predominantly T-helper (Th) 1 cell response, high interferon (IFN)-γ, interleukin-12 (IL-12). UC exhibits mainly a Th2 response, dominated by IL-5 and IL-13 production. However, both conditions share the same end-stage effector pathways of tissue damage, featuring enhanced IL-21 production [1].

Evidence suggests that IL-21 is associated with the development of IBD in humans. IL-21, a member of the IL-2 family of cytokines, is mainly expressed by CD4 + Th cells, including Th1, Th2, and Th17 cells. IL-21 controls the immune process by (a) improving the clonal expansion of antigen-activated naive CD4 + and CD8 + T-cells, (b) inducing the expression of genes encoding the receptors IL-12R, IL-18R, IL-2Rɑ, and IFN-γ, Th1-associated transcription factor T-bet in activated memory T-cells, (c) promoting human natural killer (NK) cell maturation and activation, (d) regulating the differentiation and antibody production of B-cells, (e) stimulating stromal cells to produce tissue-degrading proteases, and (f) improving the secretion of T-cell chemoattractant macrophage inflammatory protein-3a by intestinal epithelial cells [2], [3], [4]. However, the results of different IL-21 studies on the pathogenesis of IBD contradict each other. IL-21 has been shown to provoke colonic inflammation, and its neutralization may have therapeutic potential for patients with IBD [5]. Other studies have shown that IL-21/IL-21R signaling can suppress intestinal inflammation in Dextran Sulfate Sodium (DSS)-induced colitis in mice through suppression of Th1 and activating Th2 and Treg responses. Recombinant IL-21 administration improved DSS-induced colitis, suggesting that manipulation of IL-21/IL-21R activity may play a role in the management of IBD [6], [7].

IL-19 and IL-24 belong to the IL-10 family of cytokines and induce the expression of pro-inflammatory cytokines via the Janus Kinase 1-signal transducer and activator of transcription 3 (JAK1-STAT3) and the suppressor of cytokine signaling-3 pathways [8]. Human IL-24 induces the expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and IL-6 in monocytes. In vivo, IL-24 is predominantly expressed by skin tissue cells in inflammatory conditions, such as psoriasis. IL-24 can enhance the expression of mucins, supporting its suppressive effects on mucosal inflammation in IBD. The number of IL-24-expressing cells in the inflamed colonic tissue from patients with UC was higher than that in the non-inflamed colonic tissue from patients with UC or healthy controls. These findings suggest a role for IL-24 in the pathogenesis of UC [9], [10].

IL-19 is produced by keratinocytes, epithelial cells, monocytes, and B cells. Binding to its heterodimeric receptor complex (IL-20Ra/IL-20Rb) activates STAT1 and STAT3 in the STAT pathway. The role of IL-19 has been investigated mainly in patients with psoriasis, who had increased IL-19 levels in keratinocytes from affected skin areas, suggesting that IL-19 likely contributes to the inflammatory process. Limited evidence has demonstrated that IL-19 can participate in the control of the inflammatory process and potentially induce mucosal healing in experimental models of colitis in mice [10]. Certain IL-19 polymorphisms have a protective effect on UC [11], [12]. Recent research has shown increased expression of IL-19 in intestinal and colon biopsies of patients with CD compared with healthy controls and patients with UC [11], [13].

IL-33 is a newly described member of the IL-1 family. It is expressed in various nonhemopoietic cells, certain populations of inflammatory cells, and epithelial cells of the intestinal mucosa. It helps maintain gut homeostasis [14], [15], [16], [17]. IL-33 has a dual function: as a pro-inflammatory cytokine, primarily inducing the Th2 cell response, and as a regulatory cytokine, alerting the immune system to danger or tissue damage when released from injured epithelial cells. IL-33 levels increased in parasitic infections of the gastrointestinal tract and active UC [18], [19], [20], [21], [22], [23].

In this review, our objective was to describe the expression of these ILs in the intestinal mucosa of patients with UC and CD and their effect in experimental models of IBD. We will also discuss their effect on adaptive immunity in the bowel and whether they can be used as biomarkers in active disease or as potential therapeutic targets.