Expression and function of the bile acid receptor TGR5 in Kupffer cells

https://doi.org/10.1016/j.bbrc.2008.04.171Get rights and content

Abstract

Kupffer cells are resident macrophages in the liver and play a central role in the hepatic response to injury. Bile acids can impair macrophage function leading to decreased cytokine release. TGR5 is a novel, membrane-bound bile acid receptor, and it has been suggested that the immunosuppressive effect of bile acids can be mediated by TGR5. However, the function of TGR5 in Kupffer cells has not been studied and a direct link between TGR5 and cytokine production in macrophages has not been established. The present study demonstrates that TGR5 is localized in the plasma membrane of isolated Kupffer cells and is responsive to bile acids. Furthermore, bile acids inhibited LPS-induced cytokine expression in Kupffer cells via TGR5-cAMP dependent pathways. TGR5-immunoreactivity in Kupffer cells was increased in rat livers following bile-duct ligation, suggesting that TGR5 may play a protective role in obstructive cholestasis preventing excessive cytokine production thereby reducing liver injury.

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Materials and methods

Materials. Cell culture media were from Gibco (Invitrogen, Karlsruhe, Germany). Penicillin/streptomycin were from Biochrom (Berlin, Germany). Foetal calf serum was from PAA (Coelbe, Germany). Taurocholate, taurolithocholate, oleanoloic acid were from Sigma–Aldrich (Taufkirchen, Germany). The TGR5 agonist BR27 was a gift from the Bayer AG (Leverkusen, Germany).

Antibodies. Polyclonal antibodies were raised in guinea pigs (M38) and rabbits (K36) against amino acids 306–329 from the C-terminus of

Localization of TGR5 in rat liver

Immunolocalization of TGR5 was studied in rat livers using an antibody directed against the C-terminus of rat TGR5 [11]. TGR5-immunoreactivity was detected in sinusoidal endothelial cells and in Kupffer cells (KC); the latter was shown by the co-localization of the TGR5 specific staining with the CD163 (ED2) fluorescence pattern, a common marker protein of KC (Fig. 1A–C). Furthermore, TGR5 was localized in cytokeratin-19 (CK19)-expressing bile-ducts [22], as demonstrated by the co-localization

Discussion

As shown previously, the bile acid receptor TGR5 is expressed in sinusoidal endothelial cells (SEC), where bile acids induced expression of eNOS mRNA and increased NO production [11]. Expression of TGR5 was also found in Kupffer cells (KC) [11], but the functional significance of TGR5 in KC remained unclear to date. The present study addressed this issue and demonstrates that TGR5 is localized in the plasma membrane of isolated KC and is activated in response to bile acids leading to increased

Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 575 “Experimental Hepatology” and through the Forschungskommission Düsseldorf. Expert technical assistance by Claudia Rupprecht is acknowledged.

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