Article

Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium.

UPMC Univ Paris 06, Inserm, UMR_S 893, CdR Saint Antoine, Paris, France.
Gastroenterology (impact factor: 11.68). 12/2008; 136(4):1435-43. DOI:10.1053/j.gastro.2008.12.040 pp.1435-43
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

2 different nuclear receptors
 
bile salts
 
biliary epithelial cells
 
biliary epithelium
 
biliary tract sterility
 
cathelicidin expression
 
cultured biliary epithelial cells
 
endogenous nuclear receptor expression
 
farnesoid X receptor
 
hepatic expressions
 
human biliary epithelial cells
 
human liver samples
 
inflammatory biliary diseases
 
intense immunoreactivity
 
nuclear receptors
 
primary biliary cirrhosis
 
prototypical inflammatory biliary disease
 
UDCA induce cathelicidin expression
 
various defense mechanisms
 
vitamin D receptor