Prevention of immune-mediated arthritis in cholestatic rats: involvement of endogenous glucocorticoids.
OBJECTIVE
Hyporesponsiveness of the hypothalamic-pituitary-adrenal axis to stress is implicated in the development of immune-mediated arthritis in rats. This study investigated whether the documented hyporesponsiveness of the hypothalamic-pituitary-adrenal axis in cholestatic rats predisposes them to immune-mediated arthritis.


METHODS
Bile duct-resected (BDR) and sham-resected rats were injected with either complete Freund's adjuvant (CFA; to induce immune-mediated arthritis) or incomplete Freund's adjuvant (IFA) at the time of laparotomy. Arthritis development was then assessed using a clinical arthritis score, and plasma corticosterone levels were determined.


RESULTS
CFA-injected sham-resected rats developed arthritis, whereas CFA-injected BDR rats did not. CFA- and IFA-injected BDR rats had 14- and 6-fold higher levels of plasma free corticosterone than respective sham-resected controls. In addition, CFA-injected BDR rats treated with the glucocorticoid receptor antagonist RU 486 developed severe arthritis.


CONCLUSIONS
Cholestasis because of BDR prevents the occurrence of immune-mediated arthritis and is associated with elevated plasma free corticosterone levels. Furthermore, CFA-injected BDR rats treated with RU 486 developed severe arthritis. Therefore, high-circulating glucocorticoid levels seem to result in a relative state of immunosuppression in BDR rats.
Swain
M G
MG
Department of Medicine, University of Calgary, Alberta, Canada.
Maric
M
M
D000704:Analysis of Variance; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000517:prevention & control*; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control; D001652:Bile Ducts / Q000601:surgery; D002779:Cholestasis / Q000378:metabolism* / Q000503:physiopathology; D003345:Corticosterone / Q000097:blood; D005620:Freund's Adjuvant; D005938:Glucocorticoids / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000276:immunology
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D005620:Freund's Adjuvant; D003345:Corticosterone