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Glucocorticoid receptors are downregulated in hepatic T lymphocytes in rats with experimental cholangitis
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  1. K Tjandra,
  2. T Le,
  3. M G Swain
  1. Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada T2N 1N4
  1. Correspondence to:
    Dr M G Swain, Gastrointestinal Research Group, Health Sciences Center, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 1N4;
    swain{at}ucalgary.ca

Abstract

Background and aims: Primary sclerosing cholangitis is a Th1 cytokine driven disease with a poor clinical responsiveness to glucocorticoid therapy. We have previously documented elevated circulating glucocorticoid levels in cholestatic rats and in addition have noted increased hepatic expression of the Th1 cytokine interferon γ (IFN-γ) in a rat model of cholangitis. Therefore, we examined the relationship between circulating glucocorticoid levels, hepatic IFN-γ expression, and hepatic T cell glucocorticoid receptor (GR) expression in a rat model of cholangitis to provide insight into the possible mechanism underlying hepatic T cell glucocorticoid resistance in cholangitic diseases.

Methods: Cholangitis was induced in male Sprague-Dawley rats by oral administration of low dose α-naphthylisothiocyanate (ANIT). On day 14, ANIT fed and control rats were sacrificed, serum collected, and hepatic, splenic, and peripheral blood T lymphocytes isolated for GR expression, as determined by reverse transcription-polymerase chain reaction and western blotting.

Results: Circulating glucocorticoid levels were markedly elevated in ANIT fed rats. Hepatic T lymphocyte GR mRNA and protein levels were significantly reduced in ANIT treated rats compared with controls. In contrast, GR mRNA and protein expression in splenic and circulating T lymphocytes was similar in both groups. Furthermore, reduced hepatic T cell GR expression in ANIT fed rats was associated with reduced hepatic CD4+ T cell sensitivity to dexamethasone inhibitory effects (that is, inhibition of interleukin 2 receptor expression).

Conclusion: We conclude that hepatic T lymphocyte resistance to elevated endogenous glucocorticoid levels in rats with experimental cholangitis appears, in part, to be mediated by decreased GR expression.

  • hepatic cytokines
  • primary sclerosing cholangitis
  • glucocorticoid sensitivity
  • PSC, primary sclerosing cholangitis
  • IL, interleukin
  • IL-2R, IL-2 receptor
  • IFN, interferon
  • DHEA, dehydroepiandrosterone
  • IBD, inflammatory bowel disease
  • GR, glucocorticoid receptor
  • PBC, primary biliary cirrhosis
  • ANIT, α-naphthylisothiocyanate
  • PBS, phosphate buffered saline
  • FITC, fluorescein isothiocyanate
  • PE, phycoerythrin
  • RT-PCR, reverse transcription-polymerase chain reaction
  • TNF, tumour necrosis factor
  • FACS, fluorescence activated cell sorter
  • ConA, concanavalin A
  • NK, natural killer
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • PBMC, peripheral blood mononuclear cells
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