The main goals of our study were twofold: (1) To determine if ex vivo treatment with VPR-254 reduced relevant cytokine (IL-17 and IL-21) secretion from colonic strips of mice with colitis; (2) To determine if treatment of mice with VPR-254 attenuated parameters of colitis, using three murine IBD models.
ILC3 contribute to the progression and aggravation of IBD while both IL-22 and IL-17, along with IFN-γ, are overexpressed by the dysregulation of NCR<sup>-</sup> ILC3 or NCR<sup>+</sup> ILC3 function and the bias of NCR<sup>+</sup> ILC3 towards ILC1 as well as regulatory ILC dysfunction in the pathological state.
In 6 non-IBD controls there were significantly lower levels of IL-12β (P = 0.023) and IL-23α (P = 0.046) compared to the patients with IBD at onset, and IL-22 (P = 0.088) and IL-36γ (P = 0.062) showed lower values without reaching significant differences.
The aim of this study was to assess the levels of interleukin (IL)-2, IL-21 and their receptors produced by CD4+ T cells in patients with inflammatory bowel disease.
Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan.
The targets of new therapeutic molecules in IBD must aim to restore immune dysregulation by the inhibition of proinflammatory cytokines (TNF-α, interleukin [IL]-6, IL-13, IL-17, IL-18, and IL-21) and augmentation of the effect of anti-inflammatory cytokines (IL-10, IL-11, and transforming growth factor β) and to pursue new anti-inflammatory targets, such as regulatory T-cell therapy, Smad7 antisense, Janus-activated kinase inhibition, Toll-like receptor stimulation, leukocyte adhesion, and blockade of T-cell homing via integrins and mucosal addressin cellular adhesion molecule-1.
Our data thus indicated that the HMGB1-TLR2/4-DCs-IL-23 cascade pathway enhances the functions of ILC3s to produce IL-17 and IL-22, and this signal way might play a vital role in the development of IBD.
In conclusion, our study provides new important insights regarding the biology of IL-22 and IL-22BP in the gut and indicates that protective actions of IL-22 are likely to be suboptimal in IBDs thus making IL-22BP a new relevant therapeutic target.
IL22 expression was elevated in gut mucosa from patients with IBD and colitis-associated cancer, which also exhibited increased expression of IL22R1 but not its coreceptor IL10R2.
However, genetic deficiency of IL-21 associates with inflammatory bowel diseases and blockade of IL-21 in the early phases exacerbates the disease progression in some models of rheumatoid arthritis and systemic lupus erythematosus, thus suggesting a dual role of IL-21 in the control of immune-mediated diseases.
T helper type (Th17) cytokines such as interleukin (IL)-17A and IL-22 are important in maintaining mucosal barrier function and may be important in the pathogenesis of inflammatory bowel diseases (IBDs).
Cytokine IL-6 is required in Citrobacter rodentium infection-induced intestinal Th17 responses and promotes IL-22 expression in inflammatory bowel disease.
Our results highlight characteristic differences between colitis induced by naive (CD45RB(hi)) and memory/effector (T(reg) cell-depleted CD45RB(lo)) cells and different ways that IL-22 impacts inflammatory bowel disease.
Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22.
In this article, we focus on data supporting the pathogenic role of IL-21 in human inflammatory bowel diseases and discuss preclinical studies that suggest that neutralization of IL-21 in vivo could be a new strategy to counteract the inflammatory bowel disease-related, tissue damaging immune response.
Finally, we show that IL-21 positively regulates its own expression in human intestinal CD3(+) lamina propria lymphocytes, and blockade of endogenous IL-21 in cultures of CD3(+) lamina propria lymphocytes isolated from patients with Crohn's disease, a chronic inflammatory bowel disease characterized by high IL-21, down-regulates Stat3 activation and IL-21 expression.
Using this approach, we demonstrated a therapeutic potency for IL-22-mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC).