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Leptin Downregulates Angulin-1 in Active Crohn's Disease via STAT3.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2020 Oct 22; Vol. 21 (21). Date of Electronic Publication: 2020 Oct 22. - Publication Year :
- 2020
-
Abstract
- Crohn's disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.
- Subjects :
- Adult
Biopsy
Caco-2 Cells
Case-Control Studies
Cyclic S-Oxides pharmacology
Down-Regulation
Female
Humans
Intestinal Mucosa metabolism
Intestinal Mucosa pathology
Leptin pharmacology
MARVEL Domain Containing 2 Protein metabolism
Male
Middle Aged
Pyridines pharmacology
STAT3 Transcription Factor antagonists & inhibitors
Tyrphostins pharmacology
Young Adult
Crohn Disease metabolism
Leptin metabolism
Receptors, Lipoprotein metabolism
STAT3 Transcription Factor metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 21
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33105684
- Full Text :
- https://doi.org/10.3390/ijms21217824