TY - JOUR T1 - Glucocorticoid receptors are downregulated in hepatic T lymphocytes in rats with experimental cholangitis JF - Gut JO - Gut SP - 1363 LP - 1370 DO - 10.1136/gut.52.9.1363 VL - 52 IS - 9 AU - K Tjandra AU - T Le AU - M G Swain Y1 - 2003/09/01 UR - http://gut.bmj.com/content/52/9/1363.abstract N2 - 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. ER -