Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium.
OBJECTIVE
Under normal conditions, the biliary tract is a microbial-free environment. The absence of microorganisms has been attributed to various defense mechanisms that include the physicochemical and signaling actions of bile salts. Here, we hypothesized that bile salts may stimulate the expression of a major antimicrobial peptide, cathelicidin, through nuclear receptors in the biliary epithelium.


METHODS
The expression of cathelicidin was analyzed in human liver samples by immunostaining and reverse-transcription quantitative polymerase chain reaction. The regulation of cathelicidin expression by the endogenous bile salt, chenodeoxycholic acid, and by the therapeutic bile salt, ursodeoxycholic acid (UDCA), was assessed in human biliary epithelial cells in which endogenous nuclear receptor expression was blunted by siRNA or dominant-negative strategies.


RESULTS
In the human liver, biliary epithelial cells show intense immunoreactivity for cathelicidin and for the vitamin D receptor. In cultured biliary epithelial cells, chenodeoxycholic acid and UDCA induce cathelicidin expression through 2 different nuclear receptors: the farnesoid X receptor and the vitamin D receptor, respectively. Importantly, vitamin D further increases the induction of cathelicidin expression by both bile salts. In a prototypical inflammatory biliary disease (ie, primary biliary cirrhosis), we document that hepatic expressions of the vitamin D receptor and of cathelicidin significantly increased with UDCA therapy.


CONCLUSIONS
Our results indicate that bile salts may contribute to biliary tract sterility by controlling epithelial cell innate immunity. They further suggest that in inflammatory biliary diseases, which involve bacterial factors, a strategy systematically combining UDCA with vitamin D would increase therapeutic efficacy.
D'Aldebert
Emilie
E
UPMC Univ Paris 06, Inserm, UMR_S 893, CdR Saint Antoine, Paris, France.
Biyeyeme Bi Mve
Marie-Jeanne
MJ
Mergey
Martine
M
Wendum
Dominique
D
Firrincieli
Delphine
D
Coilly
Audrey
A
Fouassier
Laura
L
Corpechot
Christophe
C
Poupon
Raoul
R
Housset
Chantal
C
Chignard
Nicolas
N
D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001659:Biliary Tract / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate; D008099:Liver / Q000166:cytology; D034741:RNA, Small Interfering / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D014807:Vitamin D / Q000494:pharmacology; D054804:Cathelicidins; D000099150:Receptor, Farnesoid X-Activated
D023181:Antimicrobial Cationic Peptides; D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D005765:Gastrointestinal Agents; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014580:Ursodeoxycholic Acid; D014807:Vitamin D; D054804:Cathelicidins; D000099150:Receptor, Farnesoid X-Activated