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Interleukin-31 mediates MAP kinase and STAT1/3 activation in intestinal epithelial cells and its expression is up-regulated in inflammatory bowel disease
  1. Julia Dambacher
  1. Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany
    1. Florian Beigel
    1. Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany
      1. Julia Seiderer
      1. Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany
        1. Dirk Haller
        1. Nutrition and Food Research Center, Experiment. Nutritional Medicine, Technical University Munich, Germany
          1. Burkhard Göke
          1. Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany
            1. Christoph J. Auernhammer
            1. Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany
              1. Stephan Brand (stephan.brand{at}med.uni-muenchen.de)
              1. Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany

                Abstract

                Background/Aim: Interleukin-31 (IL-31), primarily expressed in activated lymphocytes, signals through a heterodimeric receptor complex consisting of the IL-31 receptor alpha (IL-31Ralpha) and the oncostatin M receptor (OSMR). Aim of this study was to analyze IL-31 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 analyzed 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 IL-31 receptor subunits, while their expression was low in unstimulated primary murine IEC. LPS and the proinflammatory cytokines TNF-alpha, IL-1beta, IFN-gamma and sodium butyrate stimulation increased IL-31, IL-31Ralpha and OSMR mRNA expression, while IL-31 itself enhanced IL-8 expression in IEC. IL-31 mediates ERK-1/2, Akt, STAT1 and STAT3 activation in IEC. At low cell density, IL-31 had significant antiproliferative capacities (p<0.005). IL-31 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 analyzed: n=88).

                Conclusion: IEC express the functional IL-31 receptor complex. IL-31 modulates cell proliferation and migration suggesting a role in the regulation of intestinal barrier function particularly in intestinal inflammation.

                • Crohn's disease
                • IL-31
                • cell migration
                • cell proliferation
                • inflammatory bowel disease

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