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-6RΔIEC mice) did not display increased susceptibility to acute dextran sulfate sodium (DSS)-induced colitis. In the azoxymethane DSS model IL-6RΔIEC 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.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Crohn Disease/drug therapy , Tissue Inhibitor of Metalloproteinase-1/metabolism , Apoptosis/drug effects , Crohn Disease/metabolism , Humans , Infliximab , Transforming Growth Factor alpha/antagonists & inhibitors , Transforming Growth Factor alpha/metabolismSubject(s)
Antibodies, Monoclonal/pharmacology , Crohn Disease/drug therapy , Immunoglobulin G/pharmacology , T-Lymphocyte Subsets/drug effects , Etanercept , Humans , Immunity, Mucosal/drug effects , Infliximab , Intestinal Mucosa/immunology , Receptors, Tumor Necrosis Factor , Signal Transduction/drug effectsABSTRACT
Conventional treatment of chronic inflammatory disorders, including inflammatory bowel diseases, employs broad-range anti-inflammatory drugs. In order to reduce the side-effects and increase the efficacy of treatment, several strategies have been developed in the last decade to interfere with intercellular and intracellular inflammatory signalling processes. The highly conserved mitogen-activated protein kinase pathways regulate most cellular processes, particularly defence mechanisms such as stress reactions and inflammation. In this review, we provide an overview of the current knowledge of the specificity and interconnection of mitogen-activated protein kinase pathways, their functions in the gut immune system and published and ongoing studies on the role of mitogen-activated protein kinases in inflammatory bowel disease. The development of mitogen-activated protein kinase inhibitors and their use for the therapy of inflammatory disorders is a paradigm of the successful bridging of the gap between basic research and clinical practice.
