Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice
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1
Natinal Defense Medical College Japan, Immunology and Microbiology, Japan
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% (w/v) UDCA for four weeks. UDCA improved hepatocyte injury and survival in concanavalin-A (Con-A)-induced hepatitis by suppressing IFN-gamma production by liver mononuclear cells (MNC), especially NK and NKT cells. UDCA also increased survival after lipopolysaccharide (LPS)-challenge; however, it decreased survival of mice following Escherichia coli (E. 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 induces potent IFN-gamma production from liver NK/NKT cells. However, unlike normal mice and immune-compromised burn-injured mice, exogenous IL-18 pretreatment did not increase the serum IFN-gamma levels after E. coli challenge in the UDCA-fed mice. Interestingly, however, glucocorticoid receptor (GR) expression was significantly upregulated in the liver MNC, especially NK and NKT cells, 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-induced IFN-gamma production. Furthermore, RU486, a GR antagonist, restored the serum IFN-gamma level in UDCA-fed mice after E. coli infection. Taken together, these results suggest that IFN-gamma-reducing immunomodulatory property of UDCA is mediated by elevated GR in the liver lymphocytes in an IL-12/18 independent manner.
Keywords:
UDCA,
LPS,
Concanavalin-A,
Glucocorticoid receptor,
Escherichia coli,
IFN- γ
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Innate immunity
Citation:
Kinoshita
M,
Miyazaki
H,
Nakashima
H and
Seki
S
(2013). Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00677
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Received:
12 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Manabu Kinoshita, Natinal Defense Medical College Japan, Immunology and Microbiology, Tokorozawa, Saitama, 359-8513, Japan, manabu@ndmc.ac.jp