The Wnt signalling pathway plays a fundamental role in intestinal epithelial proliferation and differentiation [6�C8], and the induction of Wnt ligands by macrophages has recently been reported to be critical for the repair and regeneration of other tissues [13]. Our data endorse this concept and expand it by revealing a selective profile of expression of Wnt1 and Wnt3a by M2 macrophages and not www.selleckchem.com/products/MDV3100.html by M1 cells or non-polarized macrophages. This is a consistent observation since it is observed in monocyte-derived macrophages from healthy donors and IBD patients as well as in a human cell line and suggests that a signalling pathway specifically activated by the inductor of M2 polarization, IL-4, in macrophages regulate the induction of Wnt ligands.
In this line a previous study has reported activation by Il-4 of SOX2 [21], a transcription factor that has been related to the induction of Wnt1 [22].The present study demonstrates for the first time that the induction of Wnt ligands by macrophages is selectively modulated by their phenotype. In the intestinal mucosa, macrophages are strategically positioned to maintain communication with epithelial cells [13,23,24]. In the present study co-culture of macrophages in close proximity with epithelial cells revealed that the former modulate the latter in what appeared to be a paracrine action. Specifically M2 macrophages, and not M1 or non-polarized macrophages, significantly increased the nuclear expression of ��-catenin, the central component of the canonical Wnt pathway, through Wnt1.
Interestingly, the amount of ��-catenin bound to Tcf-4, the main transcription factor involved in the expression of Wnt target genes, was also increased by M2 cells, as well as the mRNA expression of Lgr5 and c-Myc [9,25] which strongly suggests that M2 macrophages are activating the Wnt signalling pathway in epithelial cells. It has been proposed a role for the Wnt- c-Myc pathway as an intracellular molecular switch between proliferation and differentiation [8]. Our results revealed that M2 macrophages profoundly decreased AP activity in Caco-2 cells which proposes that the spontaneous differentiation of these cells along the absorptive cell lineage [26,27] is impaired by M2 macrophages. Furthermore, this effect was mediated through the activation of canonical Wnt pathways since it was prevented by destabilization of epithelial ��-catenin with XAV939 [9].
The role of Wnt signalling in diminishing enterocyte differentiation is further reinforced by showing that the exogenous administration of Wnt1 to two different cell lines, Caco-2 cells and HT29 cells, significantly reduced AP activity. As a whole our results suggest that activation of ��-catenin in epithelial cells repress the expression of genes associated with the onset of cell Drug_discovery differentiation [27]. We further analysed the pathophysiological relevance of these pathways in the mucosa of UC patients.
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