Endotoxin decreases corticotropin-releasing factor receptor 1 messenger ribonucleic acid levels in the rat pituitary.

Bacterial endotoxins produce profound activation of the hypothalamo-pituitary-adrenal axis, mediated by stimulation of hypothalamic CRF neurons. Although a number of studies have described direct pituitary actions of inflammatory mediators, the effects of inflammatory stimuli on the sensitivity of corticotropes to CRF remain to be elucidated. The aim of this study was to determine the effects of inflammatory stress on the CRF receptor 1 (CRF-R1) messenger RNA (mRNA) levels in the rat pituitary. The systemic injection of endotoxin [lipopolysaccharide (LPS); 50 microg/kg, i.v.] increased plasma concentrations of ACTH and corticosterone. Ribonuclease protection analysis of total RNA isolated from individual whole pituitaries indicated that LPS produced a significant decrease in CRF-R1 mRNA that was evident by 2 h after injection (to 57% of control) and more marked by 6 h (to 38% of control). To evaluate whether the decrease in CRF-R1 mRNA was dependent upon increased exposure to CRF and/or vasopressin (AVP), LPS was injected with an anti-CRF antiserum, a CRF receptor antagonist (Astressin), or anti-AVP antiserum. A strong inhibition of the ACTH response to LPS was produced by pretreatment with anti-CRF antiserum, Astressin, or anti-AVP antiserum. However, these treatments had no effect on the decrease in CRF-R1 mRNA produced by LPS, indicating that neither CRF nor AVP are obligatory mediators of this pituitary response. The hypothesis that LPS might have direct pituitary effects on CRF-R1 mRNA levels was tested in vitro. Indeed, decreases in CRF-R1 mRNA to 43% and 53% of the control level were observed in rat anterior pituitary cell cultures that were treated with either LPS itself or the inflammatory mediator interleukin-1beta, respectively. Collectively, these results show that CRF receptor mRNA levels in the pituitary of the rat are markedly reduced by systemic LPS treatment and that this decrease is not dependent upon increased exposure of the pituitary to CRF or AVP, but may involve direct effects within the pituitary of either LPS itself or ensuing cytokine production.