GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells.

Guiyu Lou,Donna Yu,Wenyu Zhang,Xiaoxiao Ma,Yan-Dong Wang,Zhipeng Meng,Rongzhen Xu,Wendong Huang,Xianghui Fu,Carl Van Ness,Christina Bursill

doi:10.1371/journal.pone.0093567

Guiyu Lou, Donna Yu + Show 9 more

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https://doi.org/10.1371/journal.pone.0093567

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Abstract

GPBAR1/TGR5 is a novel plasma membrane-bound G protein–coupled bile acid (BA) receptor. BAs are known to induce the expression of inflammatory cytokines in the liver with unknown mechanism. Here we show that without other external stimuli, TGR5 activation alone induced the expression of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) in murine macrophage cell line RAW264.7 or murine Kupffer cells. The TGR5-mediated increase of pro-inflammatory cytokine expression was suppressed by JNK inhibition. Moreover, the induced pro-inflammatory cytokine expression in mouse liver by 1% cholic acid (CA) diet was blunted in JNK−/− mice. TGR5 activation by its ligands enhanced the phosphorylation levels, DNA-binding and trans-activities of c-Jun and ATF2 transcription factors. Finally, the induced pro-inflammatory cytokine expression in Kupffer cells by TGR5 activation correlated with the suppression of Cholesterol 7α-hydroxylase (Cyp7a1) expression in murine hepatocytes. These results suggest that TGR5 mediates the BA-induced pro-inflammatory cytokine production in murine Kupffer cells through JNK-dependent pathway. This novel role of TGR5 may correlate to the suppression of Cyp7a1 expression in hepatocytes and contribute to the delicate BA feedback regulation.

Highlights

TGR5 is a plasma membrane-bound G protein–coupled bile acid (BA) receptor, which displays varied levels of expression in different tissues [1,2,3]
These results demonstrated that TGR5 activation induced interleukin 1b (IL-1b) and tumor necrosis factor-a (TNF-a) expression in both macrophage cell line and Kupffer cells
Our results demonstrate that activation of the TGR5 by its ligand in the absence of other pro-inflammatory stimuli such as LPS, leads to the up-regulation of IL-1b and TNF-a expression in murine Kupffer cells

Summary

Introduction

TGR5 is a plasma membrane-bound G protein–coupled bile acid (BA) receptor, which displays varied levels of expression in different tissues [1,2,3]. Emerging evidence shows that TGR5 regulates glucose homeostasis, increases energy expenditure in brown adipose tissue and contributes to BA homeostasis [4,5,6]. Another well-defined function of TGR5 is its potent anti-inflammatory effect. Expression of TGR5 is detected in macrophages, including Kupffer cells in the liver [7]. THP-1 cells over-expressing TGR5 suppress the cytokine production induced by lipopolysaccharide (LPS) challenge [1]. In vivo study demonstrates that activation of TGR5 decreases LPS-induced inflammation in the liver [8] as well as inflammation in atherosclerotic plaque [9]. The physiological roles of TGR5 in pro-inflammatory cytokine expression without other inflammatory stimulation are still unknown

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