Prevention of immune-mediated arthritis in cholestatic rats: involvement of endogenous glucocorticoids.

Abstract

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. 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. 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. 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.