title: Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice.
abstract: Although ursodeoxycholic acid (UDCA) has long been used for patients with chronic cholestatic liver diseases, particularly primary biliary cirrhosis, it may modulate the host immune response. This study investigated the effect of UDCA feeding on experimental hepatitis, endotoxin shock, and bacterial infection in mice. C57BL/6 mice were fed a diet supplemented with or without 0.3% (wt/vol) UDCA for 4 wk. UDCA improved hepatocyte injury and survival in concanavalin-A (Con-A)-induced hepatitis by suppressing IFN-γ production by liver mononuclear cells (MNC), especially NK and NKT cells. UDCA also increased survival after lipopolysaccharide (LPS)-challenge; however, it increased mortality of mice following Escherichia coli infection due to the worsening of infection. UDCA-fed mice showed suppressed serum IL-18 levels and production of IL-18 from liver Kupffer cells, which together with IL-12 potently induce IFN-γ production. However, unlike normal mice, exogenous IL-18 pretreatment did not increase the serum IFN-γ levels after E. coli, LPS, or Con-A challenge in the UDCA-fed mice. Interestingly, however, glucocorticoid receptor (GR) expression was significantly upregulated in the liver MNC of the UDCA-fed mice but not in their whole liver tissue homogenates. Silencing GR in the liver MNC abrogated the suppressive effect of UDCA on LPS- or Con-A-induced IFN-γ production. Furthermore, RU486, a GR antagonist, restored the serum IFN-γ level in UDCA-fed mice after E. coli, LPS, or Con-A challenge. Taken together, these results suggest that IFN-γ-reducing immunomodulatory property of UDCA is mediated by elevated GR in the liver lymphocytes in an IL-12/18-independent manner.
authors.affiliation: Dept. of Immunology and Microbiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513 Japan. manabu@ndmc.ac.jp.
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Takigawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Miyazaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kawarabayashi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hatsuse
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ono
authors.forename: Daizoh
authors.initials: D
authors.lastname: Saitoh
authors.forename: Shuhji
authors.initials: S
authors.lastname: Seki
authors.forename: Junji
authors.initials: J
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003208:Concanavalin A; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism; D006520:Hepatitis, Animal / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D020382:Interleukin-18 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism; D014158:Transcription, Genetic; D014580:Ursodeoxycholic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007155:Immunologic Factors; D020382:Interleukin-18; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D003208:Concanavalin A; D014580:Ursodeoxycholic Acid
keywords: Escherichia coli; IFN-γ; LPS; RU486; concanavalin-A