Chronic IL-11 Promotes Proliferation, Bmp1 Signalling and Activation of the Mucosal Alarmin IL-33 in the Colon

Background and AimsIL-33 is an IL-1 related cytokine and like IL-1a has been suggested to amplify the immune response during tissue injury. IL-33 is expressed in endothelium and mucosal epithelium and is a ligand for the receptor ST2. Recently IL-33 has been shown to be a crucial amplifier of immunity that can modulate the response in a number of models of innate-type mucosal immunity. Significantly IL-33 is involved in the development of DSS induced colitis. Additionally we have demonstrated that IL-11, a member of the IL-6 family of cytokines, is also important in DSS induced colitis and others have demonstrated an antiinflammatory role for IL-11 in intestinal inflammation. Here we examine the effects of IL11 on the normal colon and establish that IL-11 is upstream of Bmp1 and IL-33, and that it regulates mucosal proliferation via Reg3β in a STAT3-dependent manner. MethodsNormal mice were treated with 5 ug of recombinant human IL-11 (rhIL-11) every 6 hours and culled either 6 hours, 24 hours of 5 days after the initial dose. Colons were removed for mRNA and protein analysis. ResultsIL-11 is a ligand for gp130 and should initiate both the Ras/MAPK/ERK and STAT1/STAT3 signalling pathways. Chronic IL-11 treatment of normal mice activates STAT3 (Tyr705) but not ERK1/2 (Thr202/Tyr204), and acute IL-11 caused a drop in ERK1/2 activation. This is a very similar to the signalling outcome downstream of IL-11 in the gastric mucosa, where signalling emanating from gp130 activation by IL-11 is skewed towards STAT3. Expression of SOCS3, a bona fide STAT3 responsive gene, is also increased in the colon following IL-11 treatment. In the gastric antrum IL-11 treatment is pro-proliferative. The same is true of the colonic response to IL-11 with a 1.6 fold increase in the expression of the proliferation marker PCNA by immunoblot. IL-11 also caused an increase in the expression of the pro-proliferative gene Reg3β and the mRNAs involved in BMP signalling Bmp1 and Bmp1rb. However, most significantly IL-11 treatment caused a large and significant increase in the expression of IL-33 and other mediators of the innate immune response in the absence of any significant damage to the mucosa. ConclusionsColonic tissue responds to IL-11 largely by activation of STAT3 signalling. There are three major outcomes resulting from this signalling; 1) increased proliferation and expression of pro-proliferative genes, 2) increased expression of components of BMP signalling and 3) activation of IL-33 and the innate immune system.