Guest guest Posted December 16, 2008 Report Share Posted December 16, 2008 Gastroenterology [in Press] (2008) Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium. d'Aldebert E, Biyeyeme Bi Mve MJ, Mergey M, Wendum D, Firrincieli D, Coilly A, Fouassier L, Corpechot C, Poupon R, Housset C, Chignard N Abbreviations : CDCA, chenodeoxycholic acid; UDCA, ursodeoxycholic acid; FXR, farnesoid X receptor; PBC, primary biliary cirrhosis; VDR, vitamin D receptor. Correspondence : Nicolas Chignard, Ph.D.; CdR Saint-Antoine, UMR_S 893, 27 rue de Chaligny, 75571 Paris Cedex 12, France; Telephone: 33- 1-40 01 13 56; Fax: 33-1-40 01 13 52; e-mail: nicolas.chignard@... Backgrounds and Aims : Under normal conditions, the biliary tract is a microbial-free environment. The absence of microorganism 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 RT-QPCR. The regulation of cathelicidin expression by the endogenous bile salt, chenodeoxycholic acid (CDCA) 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, CDCA and UDCA induce cathelicidin expression through two different nuclear receptors, i.e. 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, i.e. primary biliary cirrhosis, we document that hepatic expressions of the vitamin D receptor and of cathelicidin significantly increase upon 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. Dave (father of (23); PSC 07/03; UC 08/03) Quote Link to comment Share on other sites More sharing options...
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