title: GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China; Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Guiyu
authors.initials: G
authors.lastname: Lou
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Fu
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America; Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Yan-Dong
authors.initials: YD
authors.lastname: Wang
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Carl
authors.initials: C
authors.lastname: Van Ness
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Donna
authors.initials: D
authors.lastname: Yu
authors.affiliation: Department of Hematology and Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Rongzhen
authors.initials: R
authors.lastname: Xu
authors.affiliation: Division of Molecular Diabetes Research, Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, United States of America.
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002460:Cell Line; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D003470:Culture Media / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D001647:Bile Acids and Salts; D003470:Culture Media; D016207:Cytokines; C513561:Gpbar1 protein, mouse; D018836:Inflammation Mediators; D016755:Proto-Oncogene Proteins c-jun; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D009828:Oleanolic Acid; D002790:Cholesterol 7-alpha-Hydroxylase; D048031:JNK Mitogen-Activated Protein Kinases
references.citation: Am J Physiol Gastrointest Liver Physiol. 2013 Mar 1;304(5):G527-35
references.pmid: 23275618
references.citation: Int Immunol. 2001 Feb;13(2):241-8
references.pmid: 11157857
references.citation: J Biol Chem. 1997 Feb 14;272(7):4631-6
references.pmid: 9020192
references.citation: Phytother Res. 2010 Mar;24(3):369-73
references.pmid: 19653193
references.citation: J Biol Chem. 2010 Feb 5;285(6):3525-3531
references.pmid: 20018859
references.citation: Biochem Biophys Res Commun. 2008 Jul 18;372(1):78-84
references.pmid: 18468513
references.citation: Mol Endocrinol. 2009 Feb;23(2):137-45
references.pmid: 19056864
references.citation: Mol Endocrinol. 2011 Jun;25(6):1066-71
references.pmid: 21454404
references.citation: Methods Mol Biol. 2005;290:91-103
references.pmid: 15361657
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2519-24
references.pmid: 17284589
references.citation: Cell Signal. 2007 Feb;19(2):251-60
references.pmid: 16996249
references.citation: Biochem J. 2006 Sep 15;398(3):423-30
references.pmid: 16724960
references.citation: Cell Metab. 2011 Dec 7;14(6):747-57
references.pmid: 22152303
references.citation: J Biol Chem. 2003 Mar 14;278(11):9435-40
references.pmid: 12524422
references.citation: Curr Pathobiol Rep. 2013 Mar 1;1(1):29-35
references.pmid: 23420103
references.citation: Am J Physiol. 1996 Aug;271(2 Pt 1):G293-303
references.pmid: 8770045
references.citation: Nature. 2006 Jan 26;439(7075):484-9
references.pmid: 16400329
references.citation: J Lipid Res. 1996 Feb;37(2):223-8
references.pmid: 9026521
references.citation: J Endocrinol. 2006 Oct;191(1):197-205
references.pmid: 17065403
references.citation: J Biol Chem. 2000 Jul 21;275(29):21805-8
references.pmid: 10823815
references.citation: Hepatology. 1992 Sep;16(3):719-23
references.pmid: 1505915
references.citation: Hepatology. 2009 Sep;50(3):861-70
references.pmid: 19582812
references.citation: Cell. 2000 Sep 15;102(6):731-44
references.pmid: 11030617
references.citation: J Biol Chem. 2001 Aug 17;276(33):30708-16
references.pmid: 11402042
references.citation: Hepatology. 2011 Oct;54(4):1421-32
references.pmid: 21735468
references.citation: Nat Cell Biol. 2002 Nov;4(11):901-6
references.pmid: 12402047
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Jan;288(1):G74-84
references.pmid: 15331348
references.citation: Cell Metab. 2009 Sep;10(3):167-77
references.pmid: 19723493
references.citation: Science. 1995 Jan 20;267(5196):389-93
references.pmid: 7824938
references.citation: J Biol Chem. 2003 Sep 5;278(36):33738-46
references.pmid: 12783872
references.citation: Hepatology. 2007 Mar;45(3):695-704
references.pmid: 17326144