IL-27 increases intestinal epithelial cell proliferation and migration and its mRNA expression is up-regulated in active Crohn's disease

Background & aims: Interleukin (IL)-27, a member of the IL-6/IL-12 cytokine family, is a heterodimeric cytokine composed of EBI3 and p28 which signals via the heterodimeric IL-27R (WSX-1)/gp130 receptor complex. IL-27 is closely related to IL-12 and IL-23. Given that gp130 expression has been shown in intestinal epithelial cells (IECs), we here analyzed whether IL-27R is also expressed in this cell type. Moreover, we characterized IL-27 expression in inflammatory bowel disease and its signal transduction including biological functions on the intestinal barrier.

Methods: IL-27 cytokine and receptor expression was studied by RT-PCR, Western blot analysis and immunohistochemical analysis. Signal transduction experiments were carried out as Western blot experiments. The effect of IL-27 on apoptosis was analyzed by flow cytometry. IL-27 mediated effects on the intestinal barrier were investigated by MTS assays and wounding assays.

Results: Using RT-PCR, we demonstrated IL-27R and gp130 expression in all colorectal cancer (CRC)-derived IEC lines analyzed. However, high IL-27R protein expression was only detected in HCT116 and DLD-1 cells which were used in the following experiments. IL-27 activated the PI3-Akt pathway as well as ERK-1/2 and p38 MAP kinases. IL-27 enhanced IEC proliferation (p=0.04) and IEC migration (p<0.0001) analyzed in wounding assays. In contrast, IL-27 had no significant effect on Fas ligand-induced apoptosis. In addition, we found an 11.7-fold increase of IL-27p28 expression in inflamed colonic biopsies of patients with active Crohn's disease (CD) compared to uninflamed biopsies taken from the same patients. In contrast, there was no transcriptional up-regulation of IL-27p28 mRNA in patients with ulcerative colitis (UC).

Conclusions: In this study, we demonstrate that the IL-27 receptor complex is expressed in IECs derived from CRC. IL-27 is an up-regulator of MAP kinases and Akt resulting in increased IEC migration and proliferation, suggesting effects on the intestinal barrier. We will further investigate if IL-27R is expressed in CRC in vivo and in primary IECs. The up-regulation of IL-27 in CD suggests a pathophysiological role of this cytokine in the disease pathogenesis.