Glucocorticoid receptors are downregulated in hepatic T lymphocytes in rats with experimental cholangitis.
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 gamma (IFN-gamma) in a rat model of cholangitis. Therefore, we examined the relationship between circulating glucocorticoid levels, hepatic IFN-gamma 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 alpha-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).


CONCLUSIONS
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.
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Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada T2N 1N4.
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D015058:1-Naphthylisothiocyanate / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D015209:Cholangitis, Sclerosing / Q000139:chemically induced / Q000378:metabolism*; D002908:Chronic Disease; D003345:Corticosterone / Q000097:blood*; D003687:Dehydroepiandrosterone / Q000097:blood*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013601:T-Lymphocytes / Q000378:metabolism*
D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015375:Receptors, Interleukin-2; D015847:Interleukin-4; D003687:Dehydroepiandrosterone; D015058:1-Naphthylisothiocyanate; D007371:Interferon-gamma; D003345:Corticosterone