TNF-α facilitates inflammation-induced glucocorticoid secretion in rats with biliary obstruction

Abstract

Aims: We investigated the role of TNF-α in inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in rats with cholestasis due to bile duct resection. Methods: Acute inflammation was induced in bile duct or sham resected rats by subcutaneous injection of carrageenan and HPA axis activation was determined by measuring plasma ACTH and corticosterone levels in the absence or presence of TNF-α inhibition. Results: Bile duct resected rats had a 2.4-fold elevation in basal circulating TNFA-α levels compared to sham resected and unoperated controls. Acute inflammation induced by carrageenan injection resulted in a significant increase in plasma ACTH and corticosterone levels in bile duct resected and control rats in the absence of significant changes in plasma TNF-α levels. However, bile duct resected rats demonstrated blunted ACTH release coupled with augmented corticosterone secretion in response to carrageenan administration compared to control rats. Inhibition of TNF-α activity by pretreating rats with a specific TNF-antiserum or pentoxifylline did not alter inflamamtion-induced ACTH secretion in bile duct resected or control rats, or corticosterone secretion in control rats. However, anti-TNF treatments significantly attenuated the inflammation-induced rise in plasma corticosterone in bile duct resected rats. Conclusions: These results indicate that inflammation in rats with biliary obstruction is associated with blunted ACTH release coupled with augmented glucocorticoid secretion facilitated by TNF-α. Furthermore, these results suggest that what have been previously considered as low level elevations in circulating TNF-α levels can facilitate adrenal glucocorticoid secretion during the inflammatory response.