Bile salts control the antimicrobial peptide cathelicidin through nuclear receptors in the human biliary epithelium.
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.
Article: Food safety.[show abstract] [hide abstract]
ABSTRACT: Food can never be entirely safe. Food safety is threatened by numerous pathogens that cause a variety of foodborne diseases, algal toxins that cause mostly acute disease, and fungal toxins that may be acutely toxic but may also have chronic sequelae, such as teratogenic, immunotoxic, nephrotoxic, and estrogenic effects. Perhaps more worrisome, the industrial activities of the last century and more have resulted in massive increases in our exposure to toxic metals such as lead, cadmium, mercury, and arsenic, which now are present in the entire food chain and exhibit various toxicities. Industrial processes also released chemicals that, although banned a long time ago, persist in the environment and contaminate our food. These include organochlorine compounds, such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (dichlorodiphenyl dichloroethene) (DDT), other pesticides, dioxins, and dioxin-like compounds. DDT and its breakdown product dichlorophenyl dichloroethylene affect the developing male and female reproductive organs. In addition, there is increasing evidence that they exhibit neurodevelopmental toxicities in human infants and children. They share this characteristic with the dioxins and dioxin-like compounds. Other food contaminants can arise from the treatment of animals with veterinary drugs or the spraying of food crops, which may leave residues. Among the pesticides applied to food crops, the organophosphates have been the focus of much regulatory attention because there is growing evidence that they, too, affect the developing brain. Numerous chemical contaminants are formed during the processing and cooking of foods. Many of them are known or suspected carcinogens. Other food contaminants leach from the packaging or storage containers. Examples that have garnered increasing attention in recent years are phthalates, which have been shown to induce malformations in the male reproductive system in laboratory animals, and bisphenol A, which negatively affects the development of the central nervous system and the male reproductive organs. Genetically modified foods present new challenges to regulatory agencies around the world because consumer fears that the possible health risks of these foods have not been allayed. An emerging threat to food safety possibly comes from the increasing use of nanomaterials, which are already used in packaging materials, even though their toxicity remains largely unexplored. Numerous scientific groups have underscored the importance of addressing this issue and developing the necessary tools for doing so. Governmental agencies such as the US Food and Drug Administration and other agencies in the USA and their counterparts in other nations have the increasingly difficult task of monitoring the food supply for these chemicals and determining the human health risks associated with exposure to these substances. The approach taken until recently focused on one chemical at a time and one exposure route (oral, inhalational, dermal) at a time. It is increasingly recognized, however, that many of the numerous chemicals we are exposed to everyday are ubiquitous, resulting in exposure from food, water, air, dust, and soil. In addition, many of these chemicals act on the same target tissue by similar mechanisms. "Mixture toxicology" is a rapidly growing science that addresses the complex interactions between chemicals and investigates the effects of cumulative exposure to such "common mechanism groups" of chemicals. It is to be hoped that this results in a deeper understanding of the risks we face from multiple concurrent exposures and makes our food supply safer.Clinical Reviews in Allergy & Immunology 11/2009; 39(2):95-141. · 3.68 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. The condition primarily affects middle-aged women. Without treatment, PBC generally progresses to cirrhosis and eventually liver failure over a period of 10-20 years. PBC is a rare disease with prevalence of less than 1/2000. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by the familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at doses of 13-15 mg/kg/day, a majority of patients with PBC have a normal life expectancy without additional therapeutic measures. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarises current knowledge on the epidemiology, ethiopathogenesis, clinical, and therapeutic aspects of PBC.Journal of Hepatology 02/2010; 52(5):745-58. · 9.26 Impact Factor