Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation

Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic... Hedgehog (Hh) signaling is essential for intestinal homeostasis and has been associated with inflammation and tissue repair. We hypothesized that Hh signaling could affect the inflammatory process in inflammatory bowel disease (IBD). For this purpose, colon specimens from the inflamed and non-inflamed mucosa of 15 patients with Crohn’s disease (CD), 15 with ulcerative colitis, and 15 controls were analyzed by immunohistochemistry and real-time PCR. The production and modulation of cytokines were measured by ELISA from culture explants. Apoptosis was assessed by TUNEL and caspase-3 activity assays. Chemotaxis was evaluated using a transwell system. Primary human intestinal and skin fibroblasts were used for analyzing migration and BrdU incorporation. Hh proteins were generally expressed at the superficial epithelium, and a marked reduction was observed in CD. In the lamina propria, Gli-1 predominantly co-localized with vimentin- and alpha-smooth muscle actin-positive cells, with lower levels observed in CD. In colon explants, Hh stimulation resulted in reduction, while blockade increased, TNF α, IL-17, and TGF β levels. Apoptotic rates were higher in inflamed samples, and they increased after Hh blockade. Levels of Gli-1 mRNA were negatively correlated with caspase-3 activity. Hh blockade increased chemoattraction of monocytes. Primary fibroblasts incorporated more BrdU, but migrated less after Hh blockade. These results suggest that Hh signaling provides a negative feedback to the lamina propria, down-regulating inflammatory cytokines, and inhibiting leukocyte migration and fibroblast proliferation, while favoring fibroblast migration. Therefore, Hh signaling is strongly implicated in the pathogenesis of intestinal inflammation, and it may represent a novel therapeutic target for IBD. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Experimental Medicine Springer Journals

Disruption of the Hedgehog signaling pathway in inflammatory bowel disease fosters chronic intestinal inflammation

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Publisher
Springer International Publishing
Copyright
Copyright © 2016 by Springer International Publishing Switzerland
Subject
Medicine & Public Health; Internal Medicine; Hematology; Oncology
ISSN
1591-8890
eISSN
1591-9528
D.O.I.
10.1007/s10238-016-0434-1
Publisher site
See Article on Publisher Site

Abstract

Hedgehog (Hh) signaling is essential for intestinal homeostasis and has been associated with inflammation and tissue repair. We hypothesized that Hh signaling could affect the inflammatory process in inflammatory bowel disease (IBD). For this purpose, colon specimens from the inflamed and non-inflamed mucosa of 15 patients with Crohn’s disease (CD), 15 with ulcerative colitis, and 15 controls were analyzed by immunohistochemistry and real-time PCR. The production and modulation of cytokines were measured by ELISA from culture explants. Apoptosis was assessed by TUNEL and caspase-3 activity assays. Chemotaxis was evaluated using a transwell system. Primary human intestinal and skin fibroblasts were used for analyzing migration and BrdU incorporation. Hh proteins were generally expressed at the superficial epithelium, and a marked reduction was observed in CD. In the lamina propria, Gli-1 predominantly co-localized with vimentin- and alpha-smooth muscle actin-positive cells, with lower levels observed in CD. In colon explants, Hh stimulation resulted in reduction, while blockade increased, TNF α, IL-17, and TGF β levels. Apoptotic rates were higher in inflamed samples, and they increased after Hh blockade. Levels of Gli-1 mRNA were negatively correlated with caspase-3 activity. Hh blockade increased chemoattraction of monocytes. Primary fibroblasts incorporated more BrdU, but migrated less after Hh blockade. These results suggest that Hh signaling provides a negative feedback to the lamina propria, down-regulating inflammatory cytokines, and inhibiting leukocyte migration and fibroblast proliferation, while favoring fibroblast migration. Therefore, Hh signaling is strongly implicated in the pathogenesis of intestinal inflammation, and it may represent a novel therapeutic target for IBD.

Journal

Clinical and Experimental MedicineSpringer Journals

Published: Sep 21, 2016

References

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