Gastroenterology

Gastroenterology

Volume 128, Issue 3, March 2005, Pages 687-694
Gastroenterology

Basic-alimentary tract
Interleukin-21 enhances T-helper cell type I signaling and interferon-γ production in Crohn’s disease

https://doi.org/10.1053/j.gastro.2004.12.042Get rights and content

Background & Aims T-helper (Th)1 cells play a central role in the pathogenesis of tissue damage in Crohn’s disease (CD). Interleukin (IL)-12/STAT4 signaling promotes Th1 cell commitment in CD, but other cytokines are needed to maintain activated Th1 cells in the mucosa. In this study, we examined the expression and role of IL-21, a T-cell–derived cytokine of the IL-2 family; in tissues and cells isolated from patients with inflammatory bowel disease. Methods IL-21 was examined by Western blotting in whole mucosa and lamina propria mononuclear cells (LPMCs) from patients with CD, ulcerative colitis (UC), and controls. We also examined the effects of exogenous IL-12 on IL-21 production, as well as the effects of blocking IL-21 with an IL-21–receptor Ig fusion protein. Interferon (IFN)-γ was measured in the culture supernatants by enzyme-linked immunosorbent assay, and phosphorylated STAT4 and T-bet were examined by Western blotting. Results IL-21 was detected in all samples, but its expression was higher at the site of disease in CD in comparison with UC and controls. Enhanced IL-21 was seen in both ileal and colonic CD and in fibrostenosing and nonfibrostenosing disease. IL-12 enhanced IL-21 in normal lamina propria lymphocytes through an IFN-γ–independent mechanism, and blocking IL-12 in CD LPMCs decreased anti-CD3–stimulated IL-21 expression. Neutralization of IL-21 in CD LPMC cultures decreased phosphorylated STAT4 and T-bet expression, thereby inhibiting IFN-γ production. Conclusions Our data suggest that IL-21 contributes to the ongoing Th1 mucosal response in CD.

Section snippets

Patients and samples

Mucosal samples were taken from freshly obtained intestinal resection specimens of 29 patients with active CD. In 18 patients the primary site of disease was the terminal ileum and in 11 patients disease was present in both the ileum and colon. Thirteen patients were receiving corticosteroids, 10 were taking corticosteroids plus azathioprine, and 6 were taking mesalazine plus antibiotics. Eighteen CD patients had a fibrostenosing disease. The indication for surgery was chronic disease,

IL-21 expression is enhanced at the site of disease in CD

IL-21 was detected in tissue homogenates from all samples regardless of whether mucosal specimens were taken from inflammatory bowel disease patients or controls. However, there was a clear increase in the intensity of the IL-21 bands in CD compared with UC patients, diverticular disease patients, and normal controls (Figure 1A). In addition, IL-21 levels were higher in UC patients than in diverticular disease and normal control patients (P < .01), whereas no difference was seen between

Discussion

This study was performed to analyze the expression and role of IL-21 in CD. We show that IL-21 is produced at a higher level in CD patients than in UC and control patients. Enhanced expression of IL-21 is seen in areas with active inflammation, with no difference between ileal and colonic samples. IL-21 was analyzed by Western blotting because no commercial kit capable of quantitatively measuring IL-21 is available yet. Western blotting is not a quantitative technique and the arbitrary units we

References (30)

  • P. Parronchi et al.

    Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn’s disease

    Am J Pathol

    (1997)
  • M.F. Neurath et al.

    Antibodies to interleukin 12 abrogate established experimental colitis in mice

    J Exp Med

    (1995)
  • S. Wirtz et al.

    Chronic intestinal inflammation in STAT-4 transgenic micecharacterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens

    J Immunol

    (1999)
  • G. Monteleone et al.

    Bioactive IL-18 expression is up-regulated in Crohn’s disease

    J Immunol

    (1999)
  • G. Monteleone et al.

    Response of human intestinal lamina propria T lymphocytes to interleukin 12additive effects of interleukin 15 and 7

    Gut

    (1998)
  • Cited by (0)

    Supported by the Fondazione Umberto di Mario, Rome, and the Broad Medical Research Program Foundation (grant IBD-00200R).

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