Il22, interleukin-22, is a cytokine that serves as a critical regulator of epithelial homeostasis [3]. It is involved in multiple aspects of epithelial barrier function, such as regulating epithelial cell growth, permeability, mucus and antimicrobial protein production, and complement production. The Il22 signaling pathway has been associated with maintaining gastrointestinal epithelial barrier function, cell proliferation, and protecting intestinal stem cells [7].

In an ileal organoid model, high levels of Il22 decreased ileal organoid survival, inhibited the expansion of intestinal stem cells (ISCs), and reduced ISC biomarker expression and self-renewal-associated pathway activity. However, resistant organoids grew larger and showed increased proliferation. Il22ra1 was expressed on only a subset of ISCs and transit-amplifying (TA) progenitors, and chronically increased Il22 levels in vivo led to increased proliferative cells in the TA zone with no increase in ISCs [1]. In allogeneic stem cell transplantation, patients not suffering from transplant-related mortality (TRM) had significantly upregulated Il22 expression during histological and clinical GI-GvHD, while lower Il22 was associated with a higher probability of TRM, and it was identified as an independent risk factor for TRM. Also, Il22 expression seemed to be microbiota-dependent [2]. In cutaneous melanoma, elevated Il22 promoted cell proliferation, migration, and invasion by driving the miR-181/STAT3/AKT axis [4]. In rat mesenchymal stem cells, Il22 furthered their malignant transformation, possibly associated with IL22RA1/STAT3 signaling [5]. In muscle-invasive bladder cancer, high infiltration of intratumoral Il22-producing cells was associated with poor prognosis, but nivolumab showed tumor-killing efficacy in such tumors [6]. In colorectal cancer, infiltration by Il22-producing T cells promoted neutrophil recruitment and predicted a favorable clinical outcome [8]. In the intestine, Il22-dependent protective responses involved O-glycan modification, proliferation, and differentiation in MATH1+ progenitor cells [9].

In conclusion, Il22 plays diverse and significant roles in maintaining epithelial homeostasis and is involved in various disease conditions such as inflammatory bowel disease, graft-versus-host disease, cancer, and allogeneic stem cell transplantation-related outcomes. The use of models like the ileal organoid model, transgenic mice, and in vitro cell-based models has provided valuable insights into the functions of Il22 in these biological processes and disease states.