Interleukin 1 β suppresses bile acid-induced BSEP expression via a CXCR2-dependent feedback mechanism

Carolin Angendohr; Leah Missing; Christian Ehlting; Stephanie D Wolf; Karl S Lang; Mihael Vucur; Tom Luedde; Johannes G Bode

doi:10.1371/journal.pone.0315243

Interleukin 1 β suppresses bile acid-induced BSEP expression via a CXCR2-dependent feedback mechanism

PLoS One. 2024 Dec 16;19(12):e0315243. doi: 10.1371/journal.pone.0315243. eCollection 2024.

Authors

Carolin Angendohr¹, Leah Missing¹, Christian Ehlting¹, Stephanie D Wolf¹, Karl S Lang², Mihael Vucur¹, Tom Luedde¹, Johannes G Bode¹

Affiliations

¹ Faculty of Medicine & Düsseldorf University Hospital, Department of Gastroenterology, Hepatology and Infectious Disease, Heinrich-Heine-University, Düsseldorf, Germany.
² Department of Immunology, University of Essen, Essen, Germany.

Abstract

Inflammation-induced cholestasis is a common problem in septic patients and results from cytokine-mediated inhibition of bile acid export including impaired expression of the bile salt export pump (BSEP) with a consecutive increase in intracellular bile acids mediating cell damage. The present study focuses on the mechanisms by which interleukin 1 β (IL-1β), as a critical mediator of sepsis-induced cholestasis, controls the expression of BSEP in hepatocytes. Notably, the treatment of hepatocytes with IL-1β leads to the upregulation of a broad chemokine pattern. Thereby, the IL-1β -induced expression of in particular the CXCR2 ligands CXCL1 and 2 is further enhanced by bile acids, whereas the FXR-mediated upregulation of BSEP induced by bile acids is inhibited by IL-1β. In this context, it is interesting to note that inhibitor studies indicate that IL-1β mediates its inhibitory effects on bile acid-induced expression of BSEP indirectly via CXCR2 ligands. Consistently, inhibition of CXCR2 with the inhibitor SB225002 significantly attenuated of the inhibitory effect of IL-1β on BSEP expression. These data suggest that part of the cholestasis-inducing effect of IL-1β is mediated via a CXCR2-dependent feedback mechanism.

Copyright: © 2024 Angendohr et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 11* / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 11* / metabolism
Animals
Bile Acids and Salts* / metabolism
Chemokine CXCL1 / genetics
Chemokine CXCL1 / metabolism
Chemokine CXCL2 / genetics
Chemokine CXCL2 / metabolism
Cholestasis / metabolism
Cholestasis / pathology
Feedback, Physiological
Hepatocytes* / drug effects
Hepatocytes* / metabolism
Humans
Interleukin-1beta* / metabolism
Mice
Phenylurea Compounds
Receptors, Cytoplasmic and Nuclear / metabolism
Receptors, Interleukin-8B* / metabolism

Substances

Receptors, Interleukin-8B
Interleukin-1beta
Bile Acids and Salts
ATP Binding Cassette Transporter, Subfamily B, Member 11
Chemokine CXCL2
Chemokine CXCL1
SB 225002
farnesoid X-activated receptor
Receptors, Cytoplasmic and Nuclear
Phenylurea Compounds

Grants and funding

This work was supported by grants from the Deutsche Forschungsgemeinschaft in particular through the collaborative research center SFB 974, project number 190586431 (JGB). Further funding came from projects of the LiSyM Network, project numbers 031L0046 (JGB) as well as the LiSyM cancer Network C-TIP HCC 031L0257G (JGB) funded by the German Federal Ministry of Education and Research. TL was funded from the European Research Council (ERC) through the ERC Consolidator Grant PhaseControl (grant agreement 771083); Deutsche Forschungsgemeinschaft (DFG): 279874820, 461704932, 440603844; the German Cancer Aid (Deutsche Krebshilfe): 70114893; and in part by the Ministry of Culture and Science of the State of North Rhine-Westphalia: NW21-062E (CANTAR), PROFILNRW-2020-107-A (MODS). CA was funded by the Clinician Scientist Program of the Forschungskommission of the medical faculty of the Heinrich-Heine University Düsseldorf.