Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis

Arthritis Rheum. 2012 Jun;64(6):1869-78. doi: 10.1002/art.34355. Epub 2011 Dec 27.


Objective: The intestinal inflammation observed in patients with ankylosing spondylitis (AS) is characterized by an overexpression of interleukin-23 (IL-23). IL-23 is known to regulate IL-22 production through lamina propria NKp44+ natural killer (NK) cells, which are thought to be involved in protective mucosal mechanisms. This study was undertaken to evaluate the frequency of NKp44+ NK cells and the expression of IL-22 in the ileum of AS patients.

Methods: Tissue NKp44+ NK cells, NKp46+ NK cells, and IL-22-producing cells were analyzed by flow cytometry. Quantitative gene expression analysis of IL-22, IL-23, IL-17, STAT-3, and mucin 1 (MUC-1) was performed by reverse transcriptase-polymerase chain reaction on ileal samples from 15 patients with AS, 15 patients with Crohn's disease (CD), and 15 healthy controls. NKp44, pSTAT-3, and IL-22 expression was analyzed by immunohistochemistry.

Results: The frequency of NKp44+ but not NKp46+ NK cells was increased in the inflamed ileum of AS patients compared to CD patients and controls. The frequency of NKp46+ NK cells was significantly increased only in CD patients. Among CD4+ lymphocytes and NKp44+ NK cell subsets, the latter were the major source of IL-22 on lamina propria mononuclear cells from AS patients. Significant up-regulation of IL-22, IL-23p19, MUC-1, and STAT-3 transcripts in the terminal ileum of patients with AS was observed. Immunohistochemical analysis confirmed the increased IL-22 and pSTAT-3 expression in inflamed mucosa from AS and CD patients.

Conclusion: Our findings indicate that overexpression of IL-22, together with an increased number of IL-22-producing NKp44+ NK cells, occurs in the gut of AS patients, where it appears to play a tissue-protective role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Female
  • Humans
  • Ileum / immunology*
  • Ileum / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukin-23 / genetics
  • Interleukin-23 / metabolism
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Male
  • Middle Aged
  • Mucin-1 / genetics
  • Mucin-1 / metabolism
  • Natural Cytotoxicity Triggering Receptor 2 / analysis*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Spondylitis, Ankylosing / immunology*
  • Spondylitis, Ankylosing / metabolism


  • Interleukin-23
  • Interleukins
  • Mucin-1
  • NCR2 protein, human
  • Natural Cytotoxicity Triggering Receptor 2
  • STAT3 Transcription Factor
  • interleukin-22