Gastroenterology

Gastroenterology

Volume 136, Issue 7, June 2009, Pages 2270-2279
Gastroenterology

Basic—Alimentary Tract
Interleukin-25 Inhibits Interleukin-12 Production and Th1 Cell-Driven Inflammation in the Gut

https://doi.org/10.1053/j.gastro.2009.02.049Get rights and content

Background & Aims

During the pathogenesis of Crohn's disease (CD), interleukin (IL)-12, a cytokine produced by mucosal CD14+ monocyte-like cells, promotes tissue-damaging T helper cell (Th) 1-mediated inflammation through mechanisms that are not fully understood. IL-25 promotes Th2 cell responses by activating major histocompatibility complex class II-positive non-T and non-B cells. Because Th1 and Th2 cells, and the cytokines they release, are often mutually antagonistic, we examined whether IL-25 affects IL-12 production or Th1 cell-mediated inflammation in the gut.

Methods

Studies were performed using colonic samples from patients and mice with peptidoglycan (PGN)-, 2,4,6-trinitrobenzenesulphonic acid (TNBS)-, or oxazolone-induced colitis. IL-25 receptor (IL-25R) levels were evaluated in intestinal lamina propria mononuclear cells by flow cytometry, and IL-25 levels were measured by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Mucosal CD14+ cells from patients with CD were incubated with IL-25 and/or lipopolysaccharide or PGN. Mice were injected with IL-25, and some mice first received injections of an IL-13 blocking antibody. Cytokines were quantified by real-time polymerase chain reaction and enzyme-linked immunosorbent assay.

Results

CD14+ cells from the mucosa of CD patients expressed IL-25R and responded to IL-25 by decreasing the synthesis of IL-12 and IL-23. IL-25 prevented PGN-induced colitis in mice. IL-25 induced IL-13 production in the colon, but IL-13 was not required for suppression of PGN colitis. IL-25 ameliorated TNBS- and oxazolone-colitis. Patients with CD or ulcerative colitis produced significantly less IL-25 compared with controls.

Conclusions

IL-25 inhibits CD14+ cell-derived cytokines and experimental colitis. IL-25 could be a useful treatment of CD and ulcerative colitis.

Section snippets

Mucosal Samples

Colonic mucosal biopsy specimens were taken from 16 patients with CD and 8 patients with ulcerative colitis (UC). Surgical specimens from 13 CD patients and 4 UC patients undergoing resection for a chronically active disease poorly responsive to medical treatment were also analyzed. Twenty-four patients with CD and 9 patients with UC were receiving corticosteroids and mesalazine, whereas the remaining patients were untreated. Additional biopsy samples were taken from 5 patients with IBD (2 CD

Intestinal Mucosal CD14+ Cells Express IL-25R and Respond to IL-25

The proportion of mucosal CD14+ cells was markedly increased in IBD LPMC compared with control LPMC (15% ± 5% vs 1% ± 0.5%, respectively). Nonetheless, the percentage of CD14+ cells that expressed IL-25R did not differ between IBD and controls (Figure 1A). CD3+ T cells expressed IL-25R, with no significant difference between IBD and controls (Figure 1B). Because in CD mucosa the CD14+ monocytes are a major source of IL-12,6 we next examined whether IL-25 inhibited IL-12 transcripts. Initially,

Discussion

In recent years, it has become evident that CD results from a dysregulated immune reaction within the intestinal wall directed against luminal antigens and is characterized by exaggerated production of Th1-associated cytokines.24, 25, 26 These advances led to the development of novel therapeutic agents that are currently being studied for their capacity to specifically target the mucosal Th1-inflammatory pathways occurring in CD patients.27

We identify a new mechanism in this paper by which

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    Conflicts of interest The authors disclose the following: G.M. has filed a patent entitled “A treatment for inflammatory diseases” (patent No. 08154101.3). The remaining authors disclose no conflicts.

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