%0 Figure %A Klag, Thomas %A Thomas, Maria %A Ehmann, Dirk %A Courth, Lioba %A Mailänder-Sanchez, Daniela %A Weiss, Thomas S. %A Dayoub, Rania %A Abshagen, Kerstin %A Vollmar, Brigitte %A E. Thasler, Wolfgang %A F. Stange, Eduard %A P. Berg, Christoph %A Malek, Nisar P. %A Zanger, Ulrich M. %A Wehkamp, Jan %D 2018 %T image_1_β-Defensin 1 Is Prominent in the Liver and Induced During Cholestasis by Bilirubin and Bile Acids via Farnesoid X Receptor and Constitutive Androstane Receptor.tif %U https://frontiersin.figshare.com/articles/figure/image_1_-Defensin_1_Is_Prominent_in_the_Liver_and_Induced_During_Cholestasis_by_Bilirubin_and_Bile_Acids_via_Farnesoid_X_Receptor_and_Constitutive_Androstane_Receptor_tif/6870518 %R 10.3389/fimmu.2018.01735.s001 %2 https://frontiersin.figshare.com/ndownloader/files/12534062 %K cholestasis %K antimicrobial peptides %K human β-defensin-1 %K hepatocytes %K bilirubin %X 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.

%I Frontiers