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Inflammation‐associated upregulation of the sulfated steroid transporter Slc10a6 in mouse liver and macrophage cell lines
Author(s) -
Kosters Astrid,
Abebe Demesew F.,
Felix Julio C.,
Dawson Paul A.,
Karpen Saul J.
Publication year - 2016
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.12609
Subject(s) - downregulation and upregulation , nuclear receptor , inflammation , chemokine , lipopolysaccharide , endocrinology , receptor , chemistry , medicine , biology , microbiology and biotechnology , immunology , biochemistry , transcription factor , gene
Aim Slc10a6, an incompletely characterized member of the SLC10A bile acid transporter family, was one of the most highly induced RNA transcripts identified in a screen for inflammation‐responsive genes in mouse liver. This study aimed to elucidate a role for Slc10a6 in hepatic inflammation. Methods Mice were treated with lipopolysaccharide (LPS; 2 mg/kg) or interleukin (IL)‐1β (5 mg/kg) for various time points. Cells were treated with LPS (1 μg/mL) at various time points, with cell signaling inhibitors, nuclear receptor ligands and Slc10a6 substrates. All mRNA levels were determined by quantitative polymerase chain reaction. Results Slc10a6 mRNA levels were upregulated in mouse liver at 2 h (7‐fold), 4 h (100‐fold) and 16 h (50‐fold) after LPS treatment, and 35‐fold by the cytokine IL‐1β (4 h). Both absence of the nuclear receptor Fxr and pretreating mice with the synthetic retinoid X receptor‐α ligand LG268 attenuated the LPS upregulation of Slc10a6 mRNA by 60–75%. In vitro , Slc10a6 mRNA was induced 30‐fold by LPS in mouse RAW264.7 macrophages in a time‐dependent manner (maximum at 8 h). The Slc10a6 substrate dehydroepiandrosterone sulfate (DHEAS) enhanced LPS induction of CCL5 mRNA, a pro‐inflammatory chemokine, by 50% in RAW264.7 cells. This effect was abrogated in the presence of anti‐inflammatory nuclear receptor ligands 9‐ cis ‐retinoic acid and dexamethasone. Conclusion Dramatic upregulation of Slc10a6 mRNA by LPS combined with enhanced LPS stimulation of CCL5 expression by the Slc10a6 substrate DHEAS in macrophages suggests that Slc10a6 function contributes to the hepatic inflammatory response.