Klag, Thomas and Thomas, Maria and Ehmann, Dirk and Courth, Lioba and Mailaender-Sanchez, Daniela and Weiss, Thomas S. and Dayoub, Rania and Abshagen, Kerstin and Vollmar, Brigitte and Thasler, Wolfgang E. and Stange, Eduard F. and Berg, Christoph P. and Malek, Nisar P. and Zanger, Ulrich M. and Wehkamp, Jan (2018) beta-Defensin 1 ls Prominent in the Liver and Induced During Cholestasis by Bilirubin and Bile Acids via Farnesoid X Receptor and Constitutive Androstane Receptor. FRONTIERS IN IMMUNOLOGY, 9: 1735. ISSN 1664-3224,
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Background & aims: Knowledge about innate antimicrobial defense of the liver is limited. We investigated hepatic expression and regulation of antimicrobial peptides with focus on the human beta defensin-1 (hBD-1). Methods: Radial diffusion assay was used to analyze antimicrobial activity of liver tissue. Different defensins including hBD-1 and its activator thioredoxin-1 (TXN) were analyzed in healthy and cholestatic liver samples by qPCR and immunostaining. Regulation of hBD-1 expression was studied in vitro and in vivo using bile duct-ligated mice. Regulation of hBD-1 via bilirubin and bile acids (BAs) was studied using siRNA. Results: We found strong antimicrobial activity of liver tissue against Escherichia coli. As a potential mediator of this antimicrobial activity we detected high expression of hBD-1 and TXN in hepatocytes, whereas other defensins were minimally expressed. Using a specific antibody for the reduced, antimicrobially active form of hBD-1 we found hBD-1 in co-localization with TXN within hepatocytes. hBD-1 was upregulated in cholestasis in a graded fashion. In cholestatic mice hepatic AMP expression (Defb-1 and Hamp) was enhanced. Bilirubin and BAs were able to induce hBD-1 in hepatic cell cultures in vitro. Treatment with siRNA and/or agonists demonstrated that the farnesoid X receptor (FXR) mediates basal expression of hBD-1, whereas both constitutive androstane receptor (CAR) and FXR seem to be responsible for the induction of hBD-1 by bilirubin. Conclusion: hBD-1 is prominently expressed in hepatocytes. It is induced during cholestasis through bilirubin and BAs, mediated by CAR and especially FXR. Reduction by TXN activates hBD-1 to a potential key player in innate antimicrobial defense of the liver.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NUCLEAR RECEPTORS; OBETICHOLIC ACID; BACTERIAL TRANSLOCATION; GENE-EXPRESSION; MICROBIOTA; REDUCTION; CIRRHOSIS; IMMUNITY; DISEASE; ALPHA; cholestasis; antimicrobial peptides; human beta-defensin-1; hepatocytes; bilirubin |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Feb 2020 13:20 |
| Last Modified: | 12 Feb 2020 13:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14205 |
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