Interleukin 31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is upregulated in inflammatory bowel disease

Gut. 2007 Sep;56(9):1257-65. doi: 10.1136/gut.2006.118679. Epub 2007 Apr 20.

Abstract

Background/aim: Interleukin 31 (IL31), primarily expressed in activated lymphocytes, signals through a heterodimeric receptor complex consisting of the IL31 receptor alpha (IL31Ralpha) and the oncostatin M receptor (OSMR). The aim of this study was to analyse IL31 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal inflammation.

Methods: Expression studies were performed by RT-PCR, quantitative PCR, western blotting, and immunohistochemistry. Signal transduction was analysed by western blotting. Cell proliferation was measured by MTS assays, cell migration by restitution assays.

Results: Colorectal cancer derived intestinal epithelial cell (IEC) lines express both IL31 receptor subunits, while their expression in unstimulated primary murine IEC was low. LPS and the proinflammatory cytokines TNF-alpha, IL1beta, IFN-gamma, and sodium butyrate stimulation increased IL31, IL31Ralpha, and OSMR mRNA expression, while IL31 itself enhanced IL8 expression in IEC. IL31 mediates ERK-1/2, Akt, STAT1, and STAT3 activation in IEC resulting in enhanced IEC migration. However, at low cell density, IL31 had significant antiproliferative capacities (p<0.005). IL31 mRNA expression was not increased in the TNFDeltaARE mouse model of ileitis but in inflamed colonic lesions compared to non-inflamed tissue in patients with Crohn's disease (CD; average 2.4-fold increase) and in patients with ulcerative colitis (UC; average 2.6-fold increase) and correlated with the IL-8 expression in these lesions (r = 0.564 for CD; r = 0.650 for UC; total number of biopsies analysed: n = 88).

Conclusion: IEC express the functional IL31 receptor complex. IL31 modulates cell proliferation and migration suggesting a role in the regulation of intestinal barrier function particularly in intestinal inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / immunology
  • Cell Line
  • Cell Movement / immunology
  • Colon / immunology
  • Cytomegalovirus Infections / immunology
  • Epithelial Cells / immunology*
  • Humans
  • Inflammatory Bowel Diseases / immunology*
  • Interferon-gamma / analysis
  • Interleukin-1beta / analysis
  • Interleukins / immunology*
  • Intestinal Mucosa / immunology
  • Intestines / cytology
  • Intestines / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / immunology*
  • Phosphorylation
  • RNA, Messenger / analysis
  • Receptors, Interleukin / analysis
  • Receptors, Oncostatin M / immunology
  • STAT Transcription Factors / immunology*
  • Tumor Necrosis Factor-alpha / analysis
  • Up-Regulation / immunology

Substances

  • IL31 protein, human
  • IL31RA protein, human
  • Interleukin-1beta
  • Interleukins
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Oncostatin M
  • STAT Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Mitogen-Activated Protein Kinases