Interleukin-1 and Corticotropin-Releasing Factor Receptors in the Hypothalamic–Pituitary–Adrenal Axis

Abstract

Interleukin-1 (IL-1) receptors were localized in mouse brain and pituitary using [125I]IL-1α and [125I]IL-1ra as radioligands. Receptor autoradiography and in situ hybridization studies demonstrated high densities and a discrete localization of IL-1 receptors and receptor mRNA, respectively, in the dentate gyrus of the hippocampus, choroid plexus, and anterior pituitary. Ether-laparotomy stress in mice resulted in a significant increase in [125I]IL-1α binding in the pituitary with no significant alterations observed in the brain; in contrast, [125I]oCRF binding in the pituitary was significantly decreased after the ether-laparotomy stress. The upregulation of IL-1 receptors in the mouse pituitary gland following ether-laparotomy stress was attenuated in a dose-dependent manner by systemic administration of corticotropin-releasing factor (CRF) receptor antagonist d-Phe12-Nle21,38 human CRF(12-41)NH2. Moreover, i.p. injection of r/h CRF resulted in a dramatic increase in [125I]IL-1α binding in the pituitary at 2 and 6 h after the injection although it did not affect [125I]IL-1α binding in the hippocampus. Pretreatment with the nonpeptide, type 1 selective CRF antagonist, CRA 1000 significantly decreased ether-laparotomy stress-induced increases of IL-1R1 mRNA levels in the pituitary. Moreover, ether-laparotomy caused a significant increase of IL-1R1 mRNA in the pituitary of wild-type mice, and this increment of IL-1R1 mRNA in the pituitary was abolished in the CRF knockout (KO) mouse group. The treatment of AtT-20 mouse pituitary adenoma cells for 24 h with neuroendocrine mediators of stress such as CRF and catecholamine receptor (β2 adrenergic) agonists produced a dose-dependent increase in cAMP and [125I]IL-1α binding.