Effects of Continuous Infusion of Interleukin 1β on Corticotropin-Releasing Hormone (CRH), CRH Receptors, Proopiomelanocortin Gene Expression and Secretion of Corticotropin, β-Endorphin and Corticosterone

Abstract

A number of recent studies suggest that interleukin 1β (IL-1β) is a major mediator of hypothalamo-pituitary-adrenal (HPA) responses following infectious aggression. We investigated whether IL-1β mediates long-term changes in HP A activity and studied the cellular regulation of the anterior pituitary. To mimic chronically elevated IL-1β production thought to occur during infectious diseases, osmotic pumps (Alzet type) were implanted in the peritoneal cavity of male rats and hIL-1β was infused continuously at rates of 1 or 3 µg/day. Effects of hIL-1β action on plasma ACTH, β-endorphin (β-EP) and corticosterone (CORT) secretion and on anterior pituitary (AP), ACTH and β-EP content were followed. In addition, hypothalamic (HT) CRH mRNA and in AP, CRH receptor (CRH-Rc) mRNA, POMC nuclear primary transcript RNA, POMC nuclear intermediate processing RNA and POMC nuclear and cytoplasmic mRNA were quantified using a highly sensitive solution hybridization nuclease protection assay. Continuous infusion of hIL-1 β stimulated the HPA axis at varying degrees. Increased HT CRH gene expression, AP POMC gene transcription, ACTH and β-EP release occurred only during the first 3 days of the treatment. A long-lasting enhancement of ACTH and β-EP synthesis and of POMC gene expression resulted from activated POMC gene transcription followed by an increased POMC mRNA stability and decreased POMC mRNA turnover. In the AP, stimulation of ACTH and β-EP secretion and POMC gene transcription disappeared after continuous IL-1β treatment, possibly in part due to a refractory process mediated by decreased CRH-Rc gene expression in corticotropes.