Reprogramming of pro-inflammatory human macrophages to an anti-inflammatory phenotype by bile acids

Cholestasis is caused by autoimmune reactions, drug-induced hepatotoxicity, viral infections of the liver and obstruction of bile ducts by tumours or gallstones. Cholestatic conditions are associated with impaired innate and... [ view full abstract ]

Cholestasis is caused by autoimmune reactions, drug-induced hepatotoxicity, viral infections of the liver and obstruction of bile ducts by tumours or gallstones. Cholestatic conditions are associated with impaired innate and adaptive immunity, including alterations of cellular functions of monocytes, macrophages, NK- and T-cells. Recently, it has been demonstrated that bile acids act as signal molecules, affecting lipopolysaccharide (LPS)-induced cytokine expression in primary human macrophages Moreover, bile acid treatment lead to an increased IL-10/IL-12 ratio that is characteristic for regulatory macrophages. Therefore we hypothesize that bile acid influence expression of genes, which generate the characteristic regulatory macrophages phenotype.

While taurolithocholate (TLC) itself has almost no effect on gene expression under control conditions, in presence of LPS it modulates expression of 202 out of 865 transcripts. Interestingly, pathway analysis revealed that TLC particularly supressed the expression of genes involved in mediating pro-inflammatory effects, phagocytosis, interactions with pathogens and autophagy as well as recruitment of neutrophils, NK cells and T cells. 

These data indicate a broad influence of bile acids on inflammatory response and immune functions in macrophages. This may contribute to the clinical observation that patients with cholestasis represent with anergy of their response to bacterial or viral infections.