Inflammation-associated upregulation of the sulfated steroid transporter Slc10a6 in mouse liver and macrophage cell lines.
OBJECTIVE
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.


CONCLUSIONS
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.
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Astrid
A
Kosters
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Demesew F
DF
Abebe
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Julio C
JC
Felix
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Paul A
PA
Dawson
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Saul J
SJ
Karpen
Slc10a6; inflammation; liver; macrophages; nuclear receptor