Transforming growth factor β (TGF-β) superfamily consists of numerous cytokins that regulate various cellular processes. TGF-β, the prototype of the family, signals through its cell surface serine/threonin kinase receptors and besides its role in cell differentiation, migration, adhesion etc. it is also able to induce epithelial-mesenchymal (EMT) transition via both Smad- pathway and MAPK- pathway. Among the different types of epithelial-mesenchymal transition, type II that is described to be associated with wound healing, tissue regeneration, organ fibrosis and is induced upon inflammatory stimuli. It can be triggered by secretion of growth factors such as TGF-β, EGF. Different endocytic routes are used for the internalization of TGF-β ligand and its receptors and these pathways can control the activity of downstream events. Internalization via clathrin-coated vesicles promotes the signaling while the caveola-mediated endocytosis plays important role in the termination of the events, although the steps of the latter event are less clear. The early endosome is considered a clue compartment in promoting the signaling. Recently published data suggest that the early endosome plays crucial role in the termination of the TGFβ signaling as well. It is not only maintain a special environment for the effective signaling but can direct the internalized cargos towards degradative pathways (multivesicular bodies, lysosomes).
In our previous work, we showed that during inflammation-induced epithelial-to-mesenchymal transition (EMT), mesenteric mesothelial cells express ED1 (pan-macrophage marker), indicating that they are transformed into macrophage-like cells. In this paper, we provide additional evidences about this transition by following the phagocytic activity and the TNFα production of mesenteric mesothelial cells during inflammation. Upon injection of India ink particles or fluorescent-labeled bioparticles (pHrodo) into the peritoneal cavity of rats pretreated with Freund's adjuvant, we found that mesothelial cells efficiently engulfed these particles. A similar increase of internalization could be observed by mesothelial cells in GM-CSF pretreated primary mesenteric culture. Since macrophages are the major producers of tumor necrosis factor, TNFα, we investigated expression level of TNFα during inflammation-induced EMT and found that TNFα was indeed expressed in these cells, reaching the highest level at the 5th day of inflammation. Since TNFα is one of the target genes of early growth response (EGR1) transcription factor, playing important role in monocyte-macrophage differentiation, expression of EGR1 in mesothelial cells was also investigated by Western blot and immunocytochemistry. While mesothelial cells did not express EGR1, a marked increase was observed in mesothelial cells by the time of inflammation. Parallel to this, nuclear translocation of EGR1 was shown by immunocytochemistry at the day 5 of inflammation. Caveolin-1 level was high and ERK1/2 became phosphorylated as the inflammation proceeded showing a slight decrease when the regeneration started. Our present data support the idea that under special stimuli, mesenteric mesothelial cells are able to transdifferentiate into macrophages, and this transition is regulated by the caveolin-1/ERK1/2/EGR1 signaling pathway.
Peritoneal cell suspension is composed of heterogeneous cell population. Macrophages are the most numerous cells among them. They can originate from different sources and can be resident, exudate and elicited. When we used Freund's adjuvant to elicit peritoneal macrophages, cells having large amount of caveolae on their plasma membrane appeared in the peritoneal wash. The number of these caveolae-rich cells increased by the time of the Freund's adjuvant treatment. Although their morphology was different form from the common macrophages, they were labelled with pan-macrophage antibodies. As the origin of these cells is unknown in this work, we tried to find out where they can originate from. Our interest turned towards the mesothelial cells. We found that the adjuvant treatment resulted in significant morphological changes in these cells and stimulate them to leave the surface of the mesentery. By the time of the adjuvant treatment, the macrophage markers expression increased in the mesothelial cells and more cells were found to detach from the mesentery. These results strongly suggest that under special stimuli mesothelial cells can leave the mesentery and differentiate into phagocytotic (macrophage-like) cells. These data raises the idea that mesothelial cells might not entirely differentiated and represent a multipotential cell lineage. To study whether this is the case we used anti-nestin antibody, which is a specific marker for multifunctional, multi-lineage progenitor cells. Mesothelial cells showed strong labelling with this antibody indicating that these cells really represent a 'young', not entirely differentiated cell population.
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