Colorectal cancer-derived intestinal epithelial cells express the functional receptor complex for IL-17F mediating MAP kinase activation and wound healing

Background & aims: Interleukin (IL)-17F is a novel proinflammatory cytokine which is a member of the IL-17 cytokine family. IL-17F mediates signal transduction via the heterodimeric IL-17RA/IL-17RC receptor complex. IL-17F is closely related to IL-17A. Both cytokines are secreted by Th17 cells which play a major role in the pathogenesis of Crohn's disease (CD) and other autoimmune diseases. Previous studies demonstrated that IL-17RA, the specific receptor for IL-17A, is expressed in intestinal epithelial cells (IECs). We therefore analyzed expression, signal transduction and potential biological functions of IL-17F in IECs.

Methods: Expression studies were performed by RT-PCR, Western blot analysis, and immunohistochemical analysis. IL-17F mediated signaling was analyzed in Western blot experiments. IEC restitution was analyzed by wounding assays in IEC monolayer cultures. Cell proliferation was measured in MTS assays. The effect of IL-17F on apoptosis was analyzed by flow cytometry.

Results: Using RT-PCR, we demonstrated expression of IL-17RA and IL-17RC in several colorectal cancer (CRC)-derived IEC lines. High IL-17RC expression was found especially in DLD-1 cells which was also confirmed by Western blot analysis and immunohistochemistry. DLD-1 cells were therefore used in the following experiments. IL-17F mediated the activation of ERK-1/2 and p38 MAP kinases and of Akt but had no significant effect on the phosphorylation levels of SAPK/JNK. IL-17F mediated signals resulted in significantly increased cell proliferation (p=0.01) and an increase of IEC restitution in wounding assays (p<0.0001). However, IL-17F had no significant effect on Fas ligand-induced apoptosis. Importantly, colonic IL-17F mRNA expression was significantly increased in inflamed colonic lesions in CD.

Conclusions: Here, we demonstrate for the first time expression of the functional IL-17F receptor complex in CRC-derived IECs. IL-17F mediates up-regulation of IEC migration and proliferation suggesting tumor promoting effects in CRC. Considering that previous studies demonstrated that IL-23 promotes tumour incidence and growth (Nature 2006; 442:461–5), we propose that some of these effects may be mediated via IL-23R-expressing Th17 cells promoting IL-17F secretion.