Classic IL-6R signalling is dispensable for intestinal epithelial proliferation and repair

K Aden; A Breuer; A Rehman; H Geese; F Tran; J Sommer; G H Waetzig; T M Reinheimer; S Schreiber; S Rose-John; J Scheller; P Rosenstiel

doi:10.1038/oncsis.2016.71

Classic IL-6R signalling is dispensable for intestinal epithelial proliferation and repair

Oncogenesis. 2016 Nov 21;5(11):e270. doi: 10.1038/oncsis.2016.71.

Authors

K Aden^{1

2}, A Breuer¹, A Rehman¹, H Geese¹, F Tran¹, J Sommer³, G H Waetzig⁴, T M Reinheimer⁵, S Schreiber^{1

2}, S Rose-John⁶, J Scheller³, P Rosenstiel¹

Affiliations

¹ Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
² First Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
³ Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
⁴ CONARIS Research Institute AG, Kiel, Germany.
⁵ Ferring Pharmaceuticals A/S, Copenhagen, Denmark.
⁶ Institute of Biochemistry, Kiel University, Kiel, Germany.

Abstract

Inflammatory bowel disease is characterized by disturbed cytokine signalling in the mucosa. Inhibition of the proinflammatory interleukin (IL)-6 pathway is a promising new therapeutic strategy, but safety concerns arise as IL-6 signalling also contributes to epithelial repair of the intestinal mucosa. To which extent IL-6 classic or trans-signalling contributes to intestinal repair remains elusive. We tested the influence of IL-6 classic signalling on intestinal repair and proliferation. Whereas IL-6 induced STAT3 phosphorylation in the colonic cancer cell lines, primary non-malignant intestinal organoids did not respond to IL-6 classic signalling. Mice deficient in intestinal IL-6R (IL-6R^ΔIEC mice) did not display increased susceptibility to acute dextran sulfate sodium (DSS)-induced colitis. In the azoxymethane DSS model IL-6R^ΔIEC mice were not protected from inflammation-induced carcinogenesis but showed comparable tumor load to wild-type mice. These data indicate that classic signalling is not the major pathway to transduce IL-6 stimuli into the intestinal epithelium.