THE CHRONIC INTRACEREBROVENTRICULAR INFUSION OF INTERLEUKIN-1-BETA ALTERS THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS OF CYCLING RATS .1. EFFECT ON LHRH AND GONADOTROPIN BIOSYNTHESIS AND SECRETION

We have previously reported that the acute injection of interleukin-1b eta (IL-1beta) into the brain ventricles of intact female rats promptl y decreases LHRH release and inhibits gene expression of this peptide in the medial preoptic area (MPOA). The present studies were therefore designed to determine whether continuous exposure to the cytokine wou ld disrupt the estrous cycle. IL-1beta was injected intracerebroventri cularly for 4-6 days at a rate of 4 ng/h. Daily vaginal smears were ob tained to follow the cycle; pituitary LH and FSH secretion were measur ed at regular intervals. Steady state levels of LH and FSH messenger R NA (mRNA) in the pituitary, and LHRH gene expression in the MPOA, were measured at the end of the treatment. Infusion of IL-1beta caused a t otal disruption of the estrous cycle, characterized by persistent smea rs indicative of the diestrous stage. When compared to animals treated with the vehicle, rats infused with IL-1beta showed a significant dec rease in circulating LH concentrations, which was accompanied by lower ed mRNA levels in the pituitary. This statistical difference (P < 0.01 ) persisted even when treated rats were compared to control in a simil ar stage of the cycle (i.e. diestrus). Plasma FSH levels remained low at all times after IL-1beta infusion but showed the expected cyclic ch anges in control animals. At the end of treatment, LHRH gene expressio n was also markedly suppressed in LHRH neurons distributed between the rostral preoptic area/organum vasculosum of the lamina terminalis and the MPOA of these animals. These results indicate that prolonged infu sion of IL-1beta into brain ventricles disrupts the estrous cycle, an event accompanied by decreased biosynthesis/release of LHRH and gonado tropins. We report in a related study that IL-1-treated rats also show increased plasma progesterone levels. However, it is improbable that this change was responsible for the interruption of the cycle describe d here; indeed we have previously observed that the central administra tion of IL-10 to intact rats resulted in an immediate blockade of the spontaneous activity of LHRH perikarya during the afternoon of proestr us and significantly decreased LHRH mRNA levels in gonadectomized anim als. Taken together, these data suggest that the primary effect of IL- 1beta is at the level of LHRH perikarya, and that the resulting interr uption of the cycle is caused by altered LHRH neuronal activity and bl unted gonadotropin secretion.