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

Julia Dambacher ¹, Florian Beigel ¹, Julia Seiderer ¹, Dirk Haller ², Burkhard Göke ¹, Christoph J. Auernhammer ¹ and Stephan Brand ^1*

¹ Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany
² Nutrition and Food Research Center, Experiment. Nutritional Medicine, Technical University Munich, Germany

^* To whom correspondence should be addressed. E-mail: stephan.brand{at}med.uni-muenchen.de.

Accepted 10 April 2007

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.

Keywords: Crohn's disease, IL-31, cell migration, cell proliferation, inflammatory bowel disease

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